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Wnt/β-catenin signaling in the development and therapeutic resistance of non-small cell lung cancer
Journal of Translational Medicine volume 22, Article number: 565 (2024)
Abstract
Wnt/β-catenin signaling is a critical pathway that influences development and therapeutic response of non-small cell lung cancer (NSCLC). In recent years, many Wnt regulators, including proteins, miRNAs, lncRNAs, and circRNAs, have been found to promote or inhibit signaling by acting on Wnt proteins, receptors, signal transducers and transcriptional effectors. The identification of these regulators and their underlying molecular mechanisms provides important implications for how to target this pathway therapeutically. In this review, we summarize recent studies of Wnt regulators in the development and therapeutic response of NSCLC.
Introduction
Lung cancer is one of the leading causes of cancer death worldwide, of which 80% to 85% is non–small cell lung cancer (NSCLC). Lung adenocarcinoma (LUAD) accounts for approximately 85% of NSCLC diagnoses, with lung squamous cell cancer (LUSC) accounting for approximately 15%, based on histological classification [1]. The 5-year survival rate for NSCLC is only 26.5% because the disease is usually metastatic at diagnosis. Metastatic NSCLC is generally incurable, as it almost always develops therapeutic resistance after an initial response [2].
The Wingless/integrase-1 (Wnt) family is a type of secreted glycoproteins which interacts with transmembrane receptors and contributes to the development and differentiation of multiple organs, including lung [3]. Wnt family proteins, of which there are 19 in humans, function as ligands to conduct a signal from the cell surface through the cytoplasm to the nucleus, thereby regulating expression of a coordinated sets of genes involved in multiple biological processes. Based on whether it relies on β-catenin for transcription activation, Wnt signaling pathways can be divided into the canonical pathway, namely Wnt/β-catenin signaling pathway, and non-canonical pathways, including Wnt/PCP pathway and Wnt/Ca2+ pathway [4]. Abnormal alterations of the Wnt/β-catenin pathway by its regulators contribute to the development and therapeutic responses of NSCLC [5].
β-catenin functions in a dual role, either as the most important nuclear effector of Wnt/β-catenin signaling, or as a cytoskeletal junction protein that maintains cell adhesion, which is critical for cadherin-based adherens junctions (AJs). These dual functions are carried out based on the transcriptional pool and the adhesive pool of β-catenin [6]. In the transcriptional pool, Wnt ligands initiate a Wnt/β-catenin signaling cascade, which involves the translocation of β-catenin from cytoplasm to nucleus and activation of target genes via T cell factor (TCF)/lymphoid enhancer-binding factor (LEF) family of transcription factors (Fig. 1). In the absence of Wnt ligands, pathway signaling is inactivated by a “destruction complex” comprised of the tumor suppressor Adenomatous Polyposis Coli (APC), the scaffolding protein AXIN, casein kinase 1α (CK1α) and glycogen synthase kinase 3 β (GSK-3β) [7]. Cytoplasmic β-catenin is sequestered in this destruction complex and sequentially phosphorylated by CK1α at Ser45 and GSK3β at Ser33/Ser37/Thr41, respectively [8]. Phosphorylated β-catenin is then recognized by E3 ubiquitin ligase β-Trcp and ubiquitinated for proteasomal degradation [7]. Without β-catenin in the nucleus, Groucho family transcription repressors bind to TCF/LEF transcription factors and inhibit the transcription of Wnt target genes. When present, Wnt ligands bind to the Frizzled (FZD) receptor family and a member of the low-density lipoprotein receptor–related protein (LRP) family, LRP5 or LRP6, to form FZD-LRP5/6 complexes. These complexes recruit the signal transducer Dishevelled (DVL) to the membrane for phosphorylation and oligomerization [9]. Phosphorylated DVL recruits AXIN and inhibits its interaction with other components of the destruction complex, thereby preventing proteasomal degradation of β-catenin [10]. Thus, the concentration of β-catenin will increase in the cytoplasm, translocating to the nucleus and forming a co-transcriptional complex with TCF/LEF, which activates the transcription of the downstream target genes which will regulate cell fate, migration, and tissue configuration [4].
In the adhesive pool, β-catenin acts as the core component of the AJs and regulates the aggregation of cadherin by directly binding to the cytoplasmic domain of E-cadherin and the actin-binding protein α-catenin, maintaining cell–cell junctions, tissue structural integrity, and homeostasis [11]. The canonical function of the AJs is to initiate and stabilize cell–cell adhesion between neighboring cells and to modulate actin dynamics at the cortical level, and dysfunctions of AJs contribute to cancer progression [12].
Epithelial‑mesenchymal transition (EMT) comprises an essential biological process during which cells fail to maintain epithelial cell polarity and acquire a mesenchymal phenotype, thus facilitating invasion and metastasis. During the early phase of EMT, loss of apical–basal polarity is often the first event to be observed and can lead to the destabilization of adhesion complexes, including AJs at the lateral membrane [13]. Wnt/β-catenin signaling is one of the most important pathways involved in the regulation of EMT. Wnt/β-catenin signaling exerts its effect on EMT through targeting and activating EMT-transcription factors SNAIL, SLUG, and TWIST which will regulate the expression of E-cadherin and N-cadherin. Wnt/β-catenin signaling can also impact EMT through AJs by other Wnt/β-catenin-targeted genes such as MMP7 and TIAM1 [14].
Wnt regulators influence Wnt/β-catenin signaling at both the transcriptional and translational level, with regulators identified that act on ligands, receptors, signal transducers and transcriptional effectors. These regulators might be proteins, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), or circular RNAs (circRNAs) [5]. miRNAs contain 20–25 nucleotides which repress translation of targeted mRNAs or target mRNA degradation [15]. LncRNAs are RNA transcripts longer than 200 nucleotides, and most of them do not encode peptides. LncRNAs encompass natural antisense transcripts, overlapping transcripts and intronic transcripts, which regulate gene expression through a variety of different mechanisms, including acting as molecular scaffolds that ‘guide’ chromatin-modifying enzymes, competing endogenous RNAs (ceRNAs) that ‘sponge’ miRNAs or proteins, facilitating or inhibiting long-range chromatin interactions, or functioning through the act of transcription itself [16]. CircRNAs are a class of single-stranded noncoding RNAs in circular form through non-canonical splicing or back-splicing manner. CircRNAs can serve as miRNA sponge in which circRNAs bind directly to the targeted miRNAs to inhibit miRNA activity, or affect alternative splicing through RNA-mediated interaction, or interact with RNA-binding proteins as protein scaffolds or antagonists [17].
Based on functional effect, Wnt regulators can be classified as positive and negative regulators. The upregulation of positive regulators and downregulation of negative regulators will promote the activation of Wnt/β-catenin signaling pathway. Aberrant Wnt regulator expression and signaling have been identified in lung cancer cell lines, animal models, and human NSCLC tissues [18,19,20,21,22,23]. Modulation of these regulators provide potential treatment strategies for patients with NSCLC, and many agents that suppress Wnt/β-catenin signaling also inhibit NSCLC cell lines [24, 25]. In this review, we mainly focus on the recent studies of regulators identified in Wnt/β-catenin signaling implicated in development and therapeutic responses of NSCLC.
Aberrant alterations of Wnt components in NSCLC
In humans, the complexity and specificity of Wnt signaling is achieved partially through 19 Wnt ligands [4]. The aberrant expression of most Wnt ligands have been found to closely correlate to the occurrence and progression of NSCLC, and are the thus potential biomarkers and drug targets for the diagnosis, prognosis, and treatment of NSCLC [26]. Overexpression of WNT2B, WNT3A and WNT5A has been found to associate with NSCLC [27, 28] (Table 1). FZD family members are a type of seven-pass transmembrane receptor (FZD1-FZD10) that belong to atypical G protein-coupled receptors (GPCRs). Specifically, FZD2 expression was found to associate with the prognosis of LUAD [29], and promoter CpG methylation of FZD2 might be related to the prognosis of LUSC [30]. Abnormal expression of many FZDs (FZD3, FZD8 and FZD9) is associated with the development of NSCLC [3]. It has been observed that patients with early-stage NSCLC carrying the SNP rs10898563 in FZD4 showed a significant increase in recurrence and mortality risk [31], and FZD4 expression might be associated with the prognosis of LUAD [29]. Knockdown of FZD8 by shRNA sensitized the lung cancer cells to chemotherapy [32]. FZD10 methylation was found to possibly relate to the prognosis of patients with LUSC [30] (Table 1).
For LRP5/6 receptor, LRP5 expression has been shown to be decreased in LUSC [33]. SNPs in LRP5 were found to associate with an higher risk of NSCLC (SNP rs3736228) and LUSC (SNP rs64843) [34]. SNP rs10845498 on LRP6 is associated with a lower risk of LUSC, whereas LRP6 rs6488507 is associated with higher risk of NSCLC in tobacco smokers [35]. For Dishevelled (DVL), upregulated expression of DVL1 and DVL3 was found in brain metastases from LUAD [36]. Overexpression of DVL1 is associated with unfavorable prognosis of patients with NSCLC [37] (Table 1).
For components of the destruction complex, AXIN1 methylation was found to correlate with radiosensitivity of lung cancer cells and clinical features of NSCLC [38, 39] (Table 1). Downregulation of AXIN1 expression was found in micropapillary-predominant LUAD, especially in cases with lymph node invasion, indicating diminished AXIN1 expression may affect the invasiveness of LUAD [40]. The intronic AXIN2 1712 + 19 variant exhibited increased mortality in Indian LUAD patients with GG genotype [41], while the heterozygous (GT) genotype showed a decreased risk of mortality [42]. AXIN2 148 C/T and 1365 C/T variants might be associated with reduced cancer susceptibility in Chinese NSCLC patients [43, 44]. Aberrant promoter methylation of AXIN2 was observed in NSCLC, and might be related to prognosis and histological subtyping of NSCLC [45]. High expression of CSNK2A1, which encodes CK1α, is an independent prognostic factor of poor survival for NSCLC patients [46] (Table 1). APC and CTNNB1 mutations were also found in NSCLC (Fig. 2). In NSCLC, APC mutations are mostly loss-of-function truncating mutations which are evenly distributed across APC gene (Fig. 2a; Supplementary Table 1); CTNNB1 mutations are mostly gain-of-function point mutations that mainly concentrate on the GSK3β/CK1α phosphorylation sites (Fig. 2b; Supplementary Table 2). The mutations on phosphorylation sites prevent the phosphorylation of β-catenin and so escape from E3 ubiquitin ligase β-Trcp and subsequent proteasomal degradation, thus leading to the accumulation of β-catenin and elevated Wnt/β-catenin signaling [47].
The positive regulators of Wnt/β-catenin signaling
Many positive regulators have been identified which act on Wnt ligands, receptors, transducers, components of β-catenin destruction complex, and β-catenin. These regulators might be overexpressed, amplified, or mutated in NSCLC cells.
Wnt ligands
The expression of multiple Wnt ligands have been found to be upregulated in NSCLC, including WNT1, WNT2B, WNT3A and WNT5A (Table 2). WNT1 transcriptional expression was upregulated by PHF8, a histone demethylase. Higher PHF8 expression was found in NSCLC and correlated with poorer overall survival in NSCLC patients. Mechanistically, PHF8 increases WNT1 transcription by targeting the promoter region of WNT1 and so removing the histone markers there [48]. WNT2B expression was upregulated by the RNA helicase DDX56 [49] and lncRNA RPPH1 [50]. DDX56 overexpression was found in LUSC and negatively associated with recurrence-free survival in LUSC patients. DDX56 increased the transcription of the target gene WNT2B through the degradation of primary miR-378a [49]. RPPH1 overexpression was negatively associated with disease progression and overall survival. Mechanistically, lncRNA RPPH1 promoted NSCLC progression through miR-326/WNT2B axis as WNT2B is a target gene of miR-326 [50]. Another lncRNA, AL139294.1, promotes WNT5A expression and oncogenic activity through suppression of miR-204-5p [51]. WNT3A expression was upregulated by PITX2 [52], ASPM [53], GOLPH3 [54], ALDOC [55] and FAIM2 [56] (Table 2). PITX2 binds directly to the promoter of WNT3A and upregulated its transcriptional expression. High PITX2 expression was found in LUAD and correlated with worse prognosis [52]. GOLPH3 is a peripheral membrane protein localized to the trans-Golgi. High expression of GOLPH3 was found in NSCLC tissues and was associated with clinicopathologic characteristics. GOLPH3 interacts with CKAP4 and increases the secretion of exosomal WNT3A, leading to a cancer stem cell (CSC)-like phenotype and metastasis in NSCLC [54]. WNT5A expression was found to be upregulated by PTS [57], circVAPA [58], E2F1 [59] and ATF4 [60] (Table 2). Higher PTS level was found in LUAD and correlated with late clinical stages and poor survival [57]. circVAPA acted as a ceRNA to up-regulate WNT5A by sponging miR-876-5p and thus activating Wnt/β-catenin signaling [58]. Intriguingly and perhaps paradoxically, WNT5A has also been reported to inhibit Wnt/β-catenin signaling in EGFR-mutant cells. In this scenario, E2F1-mediated repression of WNT5A expression promotes brain metastasis EGFR-mutant NSCLC, and high expression of E2F1 was negatively correlated with the expression of WNT5A and associated with poor outcomes in NSCLC [59].
Wnt receptors
Many positive regulators act on Wnt receptors by multiple mechanisms in NSCLC. FZD1 expression is upregulated by LINC00942 in LUAD (Table 2). Higher expression of LINC00942 was found in LUAD tissues and associated with poorer survival. Mechanically, LINC00942 functioned as a ceRNA which targets miR-5006-5p and increases the expression of its direct target FZD1 [61]. FZD4 expression was found upregulated by circRNA hsa_circ_0017109. Upregulation of this circRNA was found in NSCLC tumor and cell lines. Circ_0017109 regulated FZD4 expression by targeting miR-671-5p and finally activated Wnt/β-catenin signaling [62].
The phosphorylation of LRP5/6 recruits AXIN and GSK3β to its phosphorylated sites, leading to the disassembly of β-catenin destruction complex. As a result, β-catenin accumulate in cytoplasm which finally translocate to the nucleus and enhance the transcription of targeted genes [63]. LRP5/6 phosphorylation is upregulated by ENO1 [19] (Table 2), which is a metabolic enzyme involved in the synthesis of pyruvate. ENO1 also decreased GSK3β activity, inactivated the β-catenin destruction complex and ultimately upregulated β-catenin. Higher expression of ENO1 was found in metastatic lung cancer cell lines and patients, and associated with worse overall survival of patients with NSCLC [19]. LRP6 can directly interact with TRIP13 [64] and NINJ1 [65] (Table 2). TRIP13 is an ATPase which is highly expressed in NSCLC, correlating with advanced tumor stage and poor patient survival. TRIP13 promotes NSCLC cell proliferation and invasion through activating Wnt/β-catenin signaling [64]. NINJ1 is a 17-kDa homophilic cell adhesion molecule located in the cell membrane. NINJ1 overexpression was found to associate with poor prognosis in patients with NSCLC. Mechanistically, NINJ1 forms an assembly with LRP6 and FZD2, resulting in transcriptional upregulation of Wnt downstream target genes [65]. CD248 inhibits the interaction between LRP6 and Wnt repressors IGFBP4 and LGALS3BP, increasing Wnt/β-catenin signaling in pericytes to promote angiogenesis and tumor growth in lung cancer [66]. Ubiquitylation also participate into the regulation of LRP6. USP46 is a deubiquitylase which form complex with the catalytic USP46 and the WDR40-repeat proteins, WDR20 and UAF1. This complex increases the steady-state level of cell surface LRP6 and facilitates the assembly of LRP6 into signalosomes through the removal of sterically hindering ubiquitin chains. Alterations in USP46 mostly consisted of amplification and were commonly observed in LUSC [67].
SFRP family contains 5 members (SFRP1-5) and negatively regulate Wnt/β-catenin signaling by competing with FZD receptors to bind Wnt ligands extracellularly [68]. Dickkopf (DKK) family contains 3 members (DKK1-3) which negatively regulate Wnt/β-catenin signaling by preventing the interaction of Wnt ligands with LRP5/6 [68]. Inhibition of these negative regulators can promote the activation of Wnt/β-catenin signaling. Expression was found to be downregulated by miR-1254 [69], Rab37 [70] and exosomal-miR-1260b [71] (Table 2). miR-1254 suppresses SFRP1 expression through binding to its 3′ UTR. miR-1254 was upregulated in lung cancer tissues and promoted lung cancer cell proliferation [69]. Exosomal-miR-1260b was highly expressed in plasma of patients with LUAD and potentiated Wnt/β-catenin signaling by suppressing SFRP1 expression [71]. N6-methyladenosine (m6A) methylation is a key regulatory mechanism for gene expression and involved in multiple biological processes including cancer development [72]. SFRP2 expression was found to be regulated by m6A methylation through m6A reader HNRNPA2B1 [73] and writer METTL3 [74] (Table 2). HNRNPA2B1 regulates the maturing of miR-106b-5p through m6A methylation, so that miR-106b-5p targeted and suppressed SFRP2, activating Wnt/β-catenin signaling, and thus to aggravate the stemness and progression of LUAD [73]. SFRP2 expression was found to be negatively regulated by METTL3, which subsequently activated the Wnt/β-catenin signaling pathway in NSCLC [74]. DKK1 expression was found to be downregulated by RYR2 [75] and LINC00467 [76] (Table 2). RYR2 mutation prolongs survival of NSCLC patients via down-regulation of DKK1 expression [75]. LINC00467 promotes the development of LUAD by epigenetically silence of DKK1 [76].
Wnt transducers
The expression of signal transducer DVLs have been found to be upregulated by CtBP2 [77], TMEM88 [78], PWP1 [79] and lncRNA LINC00673-v4 [80] (Table 2). CtBP2 directly interacts with DVL1 and activates Wnt/β-catenin signaling in NSCLC cells [77]. Cytoplasmic TMEM88, rather than the membrane-localized TMEM88, promotes invasion and metastasis in NSCLC cells by binding DVLs. Higher expression of cytoplasmic TMEM88 was found to significantly associate with poorer clinical characteristics and inferior survival in patients with NSCLC [78]. PWP1 interacts with DVL2 and activates Wnt/β-catenin signaling pathway. PWP1 overexpression was found in NSCLC and correlates with poor clinical features [79]. LINC00673-v4 overexpression was associated with adverse clinical outcome. Mechanically, LINC00673-v4 enhanced the interaction between DDX3 and CK1ε and thus upregulated the phosphorylation of DVLs [80].
β-Catenin destruction complex
The β-catenin destruction complex consists of GSK-3β, APC, AXIN and two CK1α. GSK3B transcription was downregulated by AQP3 (Table 2), which is one member of the aquaporin (AQP) family and can promote the membrane exchange of water and regulate the osmotic balance [81]. The mRNA level of GSK3B is downregulated by many miRNAs through directly targeting 3’UTR of GSK3B, such as miR-19a/19b [82], miR-1246 [83], miR-1275 [84] and miR-582-3p [85] (Table 2). The protein levels of GSK3β is downregulated by lncRNA JPX [86] and PHLDA3 [87] and ARHGEF40 [88] (Table 2). JPX upregulated Twist1 by competitively sponging miR-33a-5p and subsequently induced EMT by activating Wnt/β-catenin signaling [86]. PHLDA3 encodes a small 127 amino acid protein. PHLDA3 is highly expressed in LUAD and is correlated with poor outcomes. PHLDA3 activates Wnt/β-catenin signaling through binding to GSK3β and promotes the oncogenic properties of NSCLC cells [87]. Ser 9 of GSK3β is the phosphorylation site for AKT, and the phosphorylation of this residue inactivates GSK3β. Recently, it was demonstrated that the scaffold protein AXIN allosterically protects GSK3β from phosphorylation at Ser9 by upstream kinases, which prevents accumulation of GSK3β phosphorylation (Ser9) in the Axin/GSK3β complex [89]. Thus, Ser9 phosphorylation of GSK3β does not affect Wnt/β-catenin signaling.
AXIN is another component of β-catenin destruction complex and contains two family members—AXIN1 and AXIN2. AXIN1 expression was found to be downregulated in NSCLC by Zbed3 [90], GTPBP2 [91], YTHDF2 [23], APEX1 [92] and RIF1 [93] (Table 2). Zbed3 belongs to the family of BED‐zinc finger proteins and is overexpressed in NSCLC. Zbed3 enhances lung cancer development partially by inhibiting AXIN/GSK3β-mediated downregulation of β-catenin levels [90]. YTHDF2 is a reader of N6-methyladenosine (m6A) on RNA. AXIN1 was a direct target of YTHDF2, which promoted AXIN1 mRNA decay and subsequently activated the Wnt/β-catenin signaling [23]. APEX1 regulates aberrant alternative splicing of AXIN1. APEX1 expression was upregulated in NSCLC samples and reduced cell proliferation and induce apoptosis of NSCLC cells [92]. RIF1 promoted development and CSC-like properties of NSCLC through enhancing PP1-AXIN interaction and thereby activating Wnt/β-catenin signaling [93]. AXIN2 expression was downregulated by a short peptide encoded by lncRNA DLX6-AS1, which is able to activate Wnt/β-catenin pathway in NSCLC cells [94]. MicroRNAs which downregulated APC expression include miR-4326 [95], miR-3607 [96] and miR-4739 [97] (Table 2). At the protein level, APC can be ubiquitinated by RNF115 and undergoes proteasomal degradation [98]. β-TrCP1 is an E3 ubiquitin ligase and one of the crucial components of β-catenin destruction complex. PKMYT1AR/miR-485-5p/PKMYT1 axis inhibited β-TrCP1 mediated ubiquitin degradation of β-catenin proteins, which in turn promote CSC maintenance and enhances tumorigenesis [99].
β-Catenin
In NSCLC, β-catenin is found to be regulated at the transcriptional level, translational level, and through subcellular translocation. The mRNA expression level of CTNNB1 can be upregulated by FLVCR1-AS1 [100], LINC01006 [101], lncRNA SNHG11 [102], TET [103], eIF3a [104], WSB2 [105], CIRP [106] and miR-214 [107] (Table 2). LINC01006 and lncRNA SNHG11 activate the Wnt/β-catenin pathway in LUAD cells by acting as sponges for miRNAs and elevating CTNNB1 mRNA level [101, 102]. The TET family of DNA hydroxylases mediates the final DNA demethylation through sequential oxidation reactions, thus are key executors for maintaining a hypomethylated genome state [108]. Loss of TET reprograms Wnt/β-catenin signaling through impaired demethylation of Wnt antagonizing genes (e.g., LRP4, CTNNBIP1, DACT1, and TMEM88) to promote the development of NSCLC [103]. eIF3a and WSB2 regulate the transcription of CTNNB1 [104, 105] (Table 2). CIRP (cold-inducible RNA binding protein) regulates CTNNB1 mRNA expression level by binding its mRNA [106]. miR-214 directly targets 3′-UTR of CTNNB1 to inhibit Wnt/β-catenin signaling in NSCLC cells [107].
The protein level of β-catenin in NSCLC cells is upregulated by LINC00514 [109], lncRNA ITGB1-DT [110], lncRNA UPLA1 [21], RNASEH1-AS1 [111], circEIF3I [112], circZSWIM4 [113], KDM2B [114], SETD1A [115], EHD1 [116], TRIM27 [117] and HORMAD1 [118] (Table 2). Of them, lncRNA ITGB1-DT facilitates LUAD progression through forming a positive feedback loop with ITGB1/Wnt/β-Catenin/MYC axis [110]. Desmoplakin has been found to inhibit Wnt/β-catenin signaling pathway in NSCLC [119]. LncRNA UPLA1 promoted Wnt/β-catenin signaling by binding to desmoplakin [21]. RNASEH1-AS1 exacerbated the progression of NSCLC by regulating the miR-516a-5p/FOXK1/β-catenin axis [111]. Circ-EIF3I could sponge miR-1253, which targets NOVA2 and promotes Wnt/β-catenin signaling [112]. CircZSWIM4 promotes the development of LUAD by targeting miR-370-3p and miR-873-5p to regulate FOXM1/β-catenin axis [113]. As the most well-characterized member of the mammalian C-terminal Eps15 homology (EH) domain-containing protein (EHD) family, EHD1 has been implicated in the resistance to EGFR-TKI in NSCLC through activation of PTEN/PI3K/AKT signaling [120]. Moreover, EHD1 activates a 14-3-3ζ/β-catenin/c-Myc regulatory circuit that synergistically promotes aerobic glycolysis in NSCLC [116].
The deubiquitination is closely related to Wnt/β-catenin pathway and that many regulators have been found to mediate the ubiquitination level of β-catenin, including lncRNA PKMYT1AR [99], FABP7 [121], and USP5 [122] (Table 2). Of them, the PKMYT1AR/miR-485-5p/PKMYT1 axis inhibits ubiquitin-mediated degradation of β-catenin, which in turn promotes CSC maintenance and enhances tumorigenesis in NSCLC [99]. FABP7 (fatty acid binding protein 7) is a cytoplasmic protein which is essential for lipid metabolism. FABP7 competitively inhibits the interaction between β-catenin and the components of its cytoplasmic destruction complex, thereby repressing the ubiquitination-mediated degradation of β-catenin [121]. USP5 encodes ubiquitin-specific peptidase 5, one of the deubiquitinating enzymes remove ubiquitin from target proteins. USP5 directly interacts with β-catenin, leading to deubiquitination, stabilization of β-catenin in NSCLC cells [122].
β-Catenin protein expression is also upregulated by FOXH1 [123], LRP8 [124], CBX4 [125], SMEK1 [126], JAML [127], ERCC6L [128], NOVA1 [129], SETDB1 [130], HMGB1 [131] and DEPDC1B [132] (Table 2), though the underlying molecular mechanism remains elusive. Additional regulators specifically mediate the level of active (i.e., unphosphorylated at Ser33/Ser37/Thr41) β‐catenin. Serine phosphorylation is necessary for recognition by the E3 ubiquitin ligase β-Trcp and subsequent proteasomal degradation. The active form of β-catenin is upregulated by MORC2 [133], PLAC8 [134], CCDC85B [135], KIF26B [136], TMED3 [137], ARHGEF40 [88] and tumor-intrinsic PD-L1 [138], with most of them modulated by AKT. Phosphorylation at Ser552 is able to regulate β-catenin activity. S100A4 is found to promote NSCLC tumor development through Wnt/β-catenin pathway-mediated autophagy inhibition. In this situation, S100A4 activates the Wnt/β-catenin pathway by the upregulation of the phosphorylation at Ser552 [139].
The nuclear accumulation of β-catenin is upregulated by lncRNA CBR3-AS1 [140], LINC00669 [141], MEF2D [142], ASNS [143], SRPK1 [144], Pygo2 [145], WDR74 [146], DSTN [147] and SOX9 [148] (Table 2). Of them, lncRNA CBR3-AS1 could physically interact with β-catenin and facilitate the activation of Wnt/β-catenin signaling thought promoting nuclear accumulation of β-catenin [140].
The complex of nuclear β-catenin and TCF4 transcription factor was upregulated by nuclear E-cadherin [149], Pygo1 [150], FOXP3 [151] and TRIB3 [152] (Table 2). β-catenin/TCF4 interaction was abolished by E-cadherin and was correlated with its nuclear localization, and consequently decreased β-catenin/TCF4 transcriptional activity. Subsequently, nuclear E-cadherin was a negative regulator of Wnt/β-catenin-elicited promotion of lung CSC phenotype [149]. FOXP3 can physically interact with TCF4 and β-catenin in the nucleus. High level of FOXP3 had a significant decrease in overall survival and recurrence free survival NSCLC patients [151].
The negative regulators of Wnt/β-catenin signaling
Many negative regulators have been identified which act on Wnt ligands, receptors, components of β-catenin destruction complex, and β-catenin. The expression of these regulators might be achieved by aberrant expression, mutation, methylation, and histone modifications in NSCLC cells.
Wnt ligands
Numerous negative regulators increase the transcriptional or protein level of multiple Wnt ligands, including WNT1 [153,154,155], WNT2B [156], WNT3A [157,158,159], WNT5A [160, 161], WNT5B [162] and WNT8B [160] (Table 3). WNT1 expression was increased by miR-383 [153], miR-924 [155] and TMEM100 [154] (Table 3), whose expression was significantly decreased in NSCLC tissues and cells. MiR-383 regulates NSCLC cell proliferation by directly targeting WNT1 [153]. MiR-924 blocked the progression of NSCLC by inhibiting RHBDD1/WNT1/β-catenin axis [155]. WNT2B was targeted by miR-577, which inactivated the Wnt/β-catenin pathway in NSCLC cells [156]. WNT3A expression was negatively regulated by circCCT3 [157], GPC5 [158] and GRIK3 [159] (Table 3). The expression of WNT5A and WNT8B was increased by miR-4757-3p in NSCLC cell lines [160]. The long isoform of WNT5A was targeted by miR-1253, which inhibited the proliferation and metastasis of NSCLC cells [161]. Likewise, WNT5B is negatively regulated by miR-5587-3p through binding to its 3′-UTR [162]. Taken together, these studies point to several miRNAs that function as tumor suppressors through inhibition of Wnt signaling.
Wnt receptors
Many negative regulators have been found to increase the expression or phosphorylation of Wnt receptors, including FZD4 [163], FZD7 [164], FZD8 [165] and LRP6 [166] (Table 3). miR-3127-5p increases the expression of FZD4, which promotes EMT and Wnt/β-catenin signaling in NSCLC [163]. MITF targets FZD7 promoter, and silencing MITF can promote tumor cell migration, invasion and colony formation in LUAD cells [164]. LncRNA AK126698 targets FZD8, and downregulation of lncRNA AK126698 promotes the proliferation and migration of NSCLC cells through Wnt/β-catenin pathway [165]. For LRP5/6, the phosphorylation of LRP6 was decreased by RASSF10, and downregulation of RASSF10 promotes lung cancer proliferation and invasion [166]. SFRP1, highlighted above as a negative regulator of FZD family members, is itself negatively regulated by LINC01089 [167] and miR-26a-5p [168], and downregulation of LINC01089 and miR-26a-5p was found in NSCLC. Dysregulated Rab37-SFRP1 pathway confers NSCLC stemness via the activation of Wnt/β-catenin signaling. Rab37 expression positively correlates with SFRP1 level in NSCLC patients and negatively correlated with tumor stage of NSCLC [70]. Expression of DKK1, previously discussed as a negative regulator of LRP5/6 coreceptors, was upregulated by hsa_circ_0006427 [169], hsa_circ_0018414 [22], PCBP1 [170] and CNN1 [171] (Table 3). DKK2 expression was found to be increased by LINC00326 [172] and ARHGAP9 [173]. Signal transducer DVLs were negatively regulated by the scaffolding protein WWC3 [174]. WWC3 interacts with DVLs, prevents casein kinase 1ϵ from phosphorylating DVLs, and inhibits the nuclear translocation of β-catenin, and downregulation of WWC3 was found in NSCLC [174].
β-Catenin destruction complex
Many negative regulators exert their inhibitory effects on components of the β-catenin destruction complex by regulating transcriptional activity, mRNA stability, and protein expression. GSK3β expression can be increased by circ-GSK3B [175] and HOXA4 [176] (Table 3). circ-GSK3B competitively sponges miR-3681-3p and miR-3909, leading to elevated GSK3B expression [175]. HOXA4 belongs to the Homeobox (HOX) gene family, which encode transcription factors that control cell differentiation and embryonic development [177]. HOXA4 significantly increased GSK3B expression by binding its promoter region and promoting its transcription [176]. AXIN1 expression was regulated by lncDBH-AS1 [178] and RBM47 [179] (Table 3). Silence of lncDBH-AS1 enhances proliferation of NSCLC cells by activating Wnt signaling pathway via the miR-155/AXIN1 axis [178]. The RNA-binding protein RBM47 inhibits the metastasis of NSCLC through modulation of AXIN1 mRNA stability [179]. APC was regulated by LKB1 [180] and FOXS1 [181] (Table 3). LKB1 binds to APC to suppress the Wnt/β-catenin signaling pathway [180]. FOXS1 inhibits Wnt/β-catenin signaling pathway by increasing APC expression in LUSC cells [181].
β-Catenin
Multiple negative regulators act on β-catenin by repressing its transcriptional expression, protein level, and nuclear accumulation. The mRNA expression level of CTNNB1 was found to be suppressed by miR-4429 [182], TMEM196 [183], SOX30 [184], EHMT2 [185], LHX6 [186], C/EBPα [187] and ARHGAP25 [188] (Table 3). The downregulation of these negative regulators was found in NSCLC tissues and cell lines (Table 2). LHX6 suppressed the Wnt/β-catenin pathway through silencing the transcriptional expression of CTNNB1. LHX6 expression was found to be a favorable independent prognostic factor for overall survival (OS) of LUAD patients and clinical characteristics [186].
The protein level of β-catenin was negatively regulated by miR-214-3p [189], miR-708-5p, miR-520a [190], miR-34c-5p [191], miR-100, miR-590 [192], cir-ITCH [193], circ-ZNF124 [194], DSTYK [195], EPB41 [196], PJA1 [197] and ZNF671 [198] (Table 3), and downregulation of these regulators was found in NSCLC. MiR-590 was down-regulated in NSCLC tissues and cell lines, and inhibited the Wnt/β-catenin pathway in NSCLC cells [192]. Interestingly, it was also found that miR-590 was negatively correlated with YAP1 expression NSCLC tumor tissues, and miR‑590 suppressed YAP1 expression by targeting its 3’ UTR in NSCLC cells [192]. circ-ZNF124 regulated YES1 expression by acting as a sponge of miR-498, thus restraining NSCLC development by suppressing Wnt/β-catenin signaling pathway [194]. DSTYK encodes dual serine/threonine and tyrosine protein kinase which phosphorylated the N-terminal domain of β-catenin and inhibited Wnt/β-catenin signaling, leading to the inhibition of tumorigenesis in a LUAD mouse model [195]. EPB41 forms a complex with ALDOC, leading to disassociation of the β-catenin destruction complex, reduced proteasomal degradation of β-catenin, elevated cytoplasmic accumulation, and nuclear translocation of β-catenin [196].
Multiple regulators inhibit Wnt/β-catenin signaling through regulating the ubiquitination-mediated degradation of β-catenin, including miR-489-3p [199], Shisa3 [200] and ING5 [201] (Table 3). miR-489-3p hampers the progression of NSCLC through targeting USP48 to increase the ubiquitination of β-catenin [199]. Shisa3 accelerates the degradation of β-catenin through decreasing the availability of FZDs [200]. ING5 overexpression promotes phosphorylation of β‐catenin at Ser33/37, leading to a decreased β‐catenin protein level [201]. The protein level of β‐catenin could also be manifested as active β‐catenin (unphosphorylated at Ser33/Ser37/Thr41), which is negatively regulated by miR-147b [202], and EXT1 [203].
The accumulation of nuclear β-catenin is negatively regulated by KCTD11 [204], Fibulin-3 [205], MARVELD3 [206] and RBM10 [207] (Table 3), and underexpression of these regulators was found in NSCLC. KCTD11 inhibits progression of lung cancer by binding to β-catenin [204]. MARVELD3 (MAL and relevant proteins for vesicle trafficking and membrane link domain 3) is a tight junction protein which influences EMT. Lower protein levels of MARVELD3 were observed in NSCLC samples, and associated with tumor metastasis. Mechanistically, MARVELD3 inhibits TGF-β1 induced EMT by suppressing Wnt/β-catenin signaling in NSCLC cells [206].
The interaction between nuclear β-catenin and TCF4 transcription factor was suppressed by SOX30 [208] and MYPT1 [209] (Table 3). SOX30 attenuates Wnt/β-catenin signaling via directly repressing the transcription of β-catenin or competitively binding to β-catenin [208]. SOX30 also suppresses Wnt/β-catenin signaling pathway through upregulation of desmosomal genes including DSP and JUP [210]. The TCF/LEF transcription factor was regulated by IRF8, which repressed β-catenin nuclear translocation and its activation [211].
Wnt/β-catenin signaling impacts therapeutic sensitivity and resistance of NSCLC
The abnormal activation of Wnt components and regulators influences response to several therapies for NSCLC, including targeted therapy, radiotherapy and chemotherapy.
Targeted therapy
In EGFR-mutant NSCLC, FOXM1 rs3742076_G (rs3742076) was found to confer gefitinib resistance by increasing FOXM1 protein stability through activating Wnt/β-catenin signaling pathway [20] (Table 4). Wnt inhibitory factor-1 (WIF1) is a secreted antagonist of Wnt/β-catenin signaling and binds to Wnt ligands extracellularly [68]. The status of WIF1 methylation is associated with progression free survival [212] and gefitinib response [213], possibly through regulation of this Wnt-FOXM1 axis. FLNA and ANXA2 cooperatively promotes the activation of the Wnt/β-catenin pathway, which contributes to gefitinib resistance [214]. DCLK1 expression confers EGFR-TKI resistance to LUAD through regulating Wnt/β-catenin activity [215]. Lower LHX6 expression was detected in HCC827/ER cells and re-expression of LHX6 increased erlotinib sensitivity through activating Wnt/β-catenin signaling [216]. The neurotransmitter acetylcholine (ACh) was specifically accumulated in drug-tolerant persister (DTP) cells. The upregulated ACh metabolism mediated EGFR-TKI sensitivity partially through activating Wnt/β-catenin signaling [217]. Multiple negative regulators were found to promote the activation of Wnt/β-catenin signaling in NSCLC. The expression of circFBXW7 was found to significantly downregulated in osimertinib-resistant cell lines (Table 4). circFBXW7 resensitizes resistant LUAD cells to osimertinib. Mechanistically, circFBXW7 encodes a short polypeptide, which directly interacts with β-catenin. This interaction leads to reduced stability of β-catenin by inducing ubiquitination, thereby attenuates Wnt/β-catenin signaling [218]. Other targeted therapies may also be susceptible to Wnt signaling. For example, case-level data exists showing a secondary CTNNB1 mutation correlating with failure of ALK TKIs [219].
Chemotherapy
Cisplatin (DDP) is the most widely used chemotherapeutic agent for NSCLC [220, 221]. DVL2 overexpression was found in DDP-resistant NSCLC A549 (A549/DDP) cells compared to the parental A549 cells (Table 4). Inhibition of DVL2 resensitizes DDP-resistant NSCLC cells through downregulating Wnt/β-catenin signaling [222]. RRM2 is a component of ribonucleotide reductase. Higher levels of RRM2 expression was found in A549/DDP cells. Knockdown OF RRM2 promoted the sensitivity of A549/DDP cells to cisplatin through Wnt/β-catenin signaling pathway [223]. TPX2 is a microtubule-related protein in mobile mitosis and spindle assembly [224]. Transmission of exosomal TPX2 promotes the resistance of NSCLC cells to docetaxel through increasing the protein level of β-catenin [225]. Many miRNAs have been found to involve in chemotherapy of NSCLC. miR-32 and miR-548a were poorly expressed in DDP-resistant NSCLC, re-expression of miR-32 and miRNA-548a promotes the sensitivity of NSCLC cells to cisplatin by targeting ROBO1/β-catenin axis [226]. miR-181c expression was upregulated in DDP-resistant NSCLC cells, and miR-181c negatively regulated WIF1 expression through directly binding to WIF1 (Table 4) [227].
Radiotherapy
Wnt/β‑catenin signaling has been found to associate with radiotherapeutic sensitivity and resistance of NSCLC. WNT5A expression is often upregulated in radiation-resistant NSCLC cells (Table 4). Mechanistic investigation indicated that altered WNT5A expression affects radiosensitivity of NSCLC via Wnt/β-catenin pathway [228]. Disabled-2 (Dab2) is known as a tumor suppressor and Wnt pathway inhibitor. It has been found that promoter de-methylation of Dab2 gene enhances X-Ray irradiation sensitivity of NSCLC cells [229]. Cancer-associated fibroblasts (CAFs), one main component of the tumor microenvironment, regulated DNA damage response of NSCLC cells following irradiation. Mechanistically, CAFs up-regulate and stabilize c-Myc, leading to the transcription activation of HK2 kinase, a key rate-limiting enzyme in glycolysis by activating Wnt/β-catenin pathway [230]. Therefore, CAFs contribute to the radioresistance of NSCLC cells by promoting the glycolysis in a Wnt/β-catenin signaling-dependent manner. UBE2T has been found to promote NSCLC progression [231]. Recently, it was found that UBE2T promotes radioresistance in NSCLC (Table 4). Mechanistically, UBE2T promotes EMT partially through Wnt/β-catenin signaling activation [232]. Therefore, Wnt/β-catenin signaling might be a potential target for enhancing radiotherapy sensitivity.
Immunotherapy
Aberrant activation of Wnt/β-catenin signaling promotes the escape of cancer cells from immune surveillance, inhibits T-cell infiltration, and mediates the response to immunotherapy [233, 234]. It has been shown that WNT1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in LUAD [235]. Tumor β-catenin expression is associated with immune evasion in NSCLC with high tumor mutation burden [236]. By bioinformatic analysis, DKK1 was identified as a candidate gene related to composition of tumor immune microenvironment and response to immunotherapy in LUAD patients [237]. Therefore, Wnt/β-catenin pathway might be a potential mechanism involved in the regulation of response to immunotherapy.
Potential NSCLC treatments through suppression of Wnt/β‑catenin signaling
Multiple small molecules exist which inhibit positive Wnt regulators, providing an avenue to suppress Wnt/β‑catenin signaling in NSCLC. Porcupine protein, a membrane bound O-acetyltransferase, regulates the biogenesis of Wnt ligands. The Porcupine inhibitor LGK‑974 functions by binding to Porcupine and competing with acyl-CoA, thus blocking Wnt acetylation by Porcupine and inhibiting Wnt/β‑catenin signaling [238] (Table 5). LGK-974 modifies tumor‑associated macrophages resulting in inhibition of NSCLC cells [239], with one Phase 1 study still active (NCT01351103).
Similarly, NCT-80 is an Hsp90 inhibitor which upregulates the transcription of Wnt ligands through Akt- and ERK-mediated activation of STAT3 (Table 5). NCT-80 effectively overcomes acquired resistance to chemotherapy and EGFR targeting anticancer therapy by inducing apoptosis and inhibiting EMT [240]. USP5 has also been found to be a positive regulator of Wnt/β‑catenin signaling in NSCLC. Targeting USP5 with the small molecule WP1130 induced the degradation of β-catenin, and showed markedly inhibitory effects on tumor growth and metastasis [122].
Many natural compounds inhibit the development of NSCLC through targeting Wnt/β-catenin signaling. Triptolide is a natural component extracted from Tripterygium wilfordii, a Chinese plant (Table 5). Triptolide inhibits EMT phenotype in both gefitinib-resistant [241] and taxol-resistant LUAD [242], possibly through the p70S6k/GSK3β/β-catenin signaling pathway [242], though its clinical applications are limited by severe hepatotoxicity [243]. Similarly, the triptolide derivative MRx102 significantly inhibited NSCLC proliferation through upregulating WIF1, a well-recognized negative regulator targeting Wnt ligands (Table 5) [244].
Many chemicals can inhibit the development and therapeutic resistance of NSCLC by targeting Wnt/β-catenin signaling. Ethacrynic acid, a loop diuretic, suppresses EMT of A549 cells via blocking of NDP-induced Wnt signaling [245] (Table 5). IMU1003 is an atrarate derivative which dramatically decreased the emergence of osimertinib-resistant colonies through inhibiting the nuclear localization of β-catenin [246] (Table 5).
FZD receptors are perhaps the best-validated Wnt regulators as therapeutic targets. Preclinically, SHH002-hu1 is an FZD7-targeting antibody which specifically binds FZD7-expressing NSCLC tissues and cells (Table 5). SHH002-hu1 effectively inhibits the migration and invasion of NSCLC cells by suppressing the activation of Wnt/β-catenin signaling [247, 248]. Three anti-FZD agents—OTSA101, vantictumab (OMP-185R), and ipafricept (OMB-54F28)—have entered clinical study. OTSA101 is an anti-FZD10 monoclonal antibody, and is radiolabeled to achieve an antiproliferative effect. OTSA101 has been studied clinically with indium 111 and yttrium 90 (NCT04176016 and NCT01469975) [249], and with actinium 225 preclinically [250]. Vantictumab is likewise a monoclonal antibody, binding to FZD1, 2, 5, 7, and 8, and has been studied clinically for a variety of cancers, including lung cancer (NCT01973309, NCT01957007, and NCT02005315) [251]. Lastly, ipafricept is a FZD8 “decoy” receptor, a truncated FZD8 protein fused to the Fc region of human IgG1 [252]. This decoy presumably functions by sequestering Wnt ligand, thus dampening canonical Wnt signaling. A total of four clinical studies of ipafricept have been completed with no results posted yet (NCT02069145, NCT02092363, NCT02050178, and NCT01608867).
Antisense oligonucleotide (ASO) drugs have been reported to be effective at inhibiting tumor growth both in vitro and in vivo (Table 5) [253]. LncRNA PKMYT1AR promotes CSC maintenance in NSCLC via activating Wnt signaling pathway. PKMYT1AR targeting ASO was found to dramatically inhibit tumor growth in vivo [99].
Nanoparticle formulations can improve the efficacy of existing drugs. Berberine, an isoquinoline alkaloid known for its anti-cancer and anti-inflammatory properties, shows low solubility and bioavailability (Table 5). The physiochemical functions of berberine can be largely improved by being encapsulated into liquid crystalline nanoparticles. Berberine liquid crystalline nanoparticles significantly suppresses the expression of β-catenin at both transcription and translation level [254].
Conclusions
Recent identification of multiple Wnt regulators, and their dysregulation in NSCLC, emphasize the importance of Wnt/β-catenin signaling in NSCLC development and therapeutic response. These regulators act on Wnt ligands, receptors, signal transducers, and transcriptional effectors, as well as those well-known regulators. Dysregulation of these Wnt regulators can be either genetic or epigenetic, resulting in overexpression, underexpression, or gain of function and loss of function. Multiple circRNAs and micropeptides have been found to regulate Wnt/β-catenin signaling in NSCLC. Continued study of these regulators improves our understanding of NSCLC biology and may open avenues to novel therapies through the direct targeting of Wnt/β-catenin signaling.
Availability of data and materials
The authors declare that all data supporting the findings of this study are provided in the Supplementary Data file. The GENIE Cohort v14-public dataset is publicly available through Sage Bionetworks (https://www.aacr.org/professionals/research/aacr-project-genie/aacr-project-genie-data/).
References
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.
Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, Bruno DS, Chang JY, Chirieac LR, D’Amico TA, et al. Non-small cell lung cancer, version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(5):497–530.
Skronska-Wasek W, Gosens R, Konigshoff M, Baarsma HA. WNT receptor signalling in lung physiology and pathology. Pharmacol Ther. 2018;187:150–66.
Rim EY, Clevers H, Nusse R. The Wnt pathway: from signaling mechanisms to synthetic modulators. Annu Rev Biochem. 2022;91:571–98.
Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 2014;106(1):djt356.
van der Wal T, van Amerongen R. Walking the tight wire between cell adhesion and WNT signalling: a balancing act for beta-catenin. Open Biol. 2020;10(12): 200267.
Lach RS, Qiu C, Kajbaf EZ, Baxter N, Han D, Wang A, Lock H, Chirikian O, Pruitt B, Wilson MZ. Nucleation of the destruction complex on the centrosome accelerates degradation of beta-catenin and regulates Wnt signal transmission. Proc Natl Acad Sci U S A. 2022;119(36): e2204688119.
Cantoria MJ, Alizadeh E, Ravi J, Varghese RP, Bunnag N, Pond KW, Kettenbach AN, Ahmed Y, Paek AL, Tyson JJ, et al. Feedback in the beta-catenin destruction complex imparts bistability and cellular memory. Proc Natl Acad Sci U S A. 2023;120(2): e2208787120.
Vamadevan V, Chaudhary N, Maddika S. Ubiquitin-assisted phase separation of dishevelled-2 promotes Wnt signalling. J Cell Sci. 2022;135(24):jcs260284.
Kang K, Shi Q, Wang X, Chen YG. Dishevelled phase separation promotes Wnt signalosome assembly and destruction complex disassembly. J Cell Biol. 2022;221(12): e202205069.
Liu DX, Hao SL, Yang WX. Crosstalk between beta-CATENIN-mediated cell adhesion and the WNT signaling pathway. DNA Cell Biol. 2023;42(1):1–13.
Gonzalez-Mariscal L, Miranda J, Gallego-Gutierrez H, Cano-Cortina M, Amaya E. Relationship between apical junction proteins, gene expression and cancer. Biochim Biophys Acta Biomembr. 2020;1862(9): 183278.
Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, et al. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2020;21(6):341–52.
Heuberger J, Birchmeier W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb Perspect Biol. 2010;2(2): a002915.
Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3):203–22.
Liu SJ, Dang HX, Lim DA, Feng FY, Maher CA. Long noncoding RNAs in cancer metastasis. Nat Rev Cancer. 2021;21(7):446–60.
Chen L, Shan G. CircRNA in cancer: fundamental mechanism and clinical potential. Cancer Lett. 2021;505:49–57.
Licchesi JD, Westra WH, Hooker CM, Machida EO, Baylin SB, Herman JG. Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung. Carcinogenesis. 2008;29(5):895–904.
Li HJ, Ke FY, Lin CC, Lu MY, Kuo YH, Wang YP, Liang KH, Lin SC, Chang YH, Chen HY, et al. ENO1 promotes lung cancer metastasis via HGFR and WNT signaling-driven epithelial-to-mesenchymal transition. Cancer Res. 2021;81(15):4094–109.
Guan S, Chen X, Chen Y, Xie W, Liang H, Zhu X, Yang Y, Fang W, Huang Y, Zhao H, et al. FOXM1 variant contributes to gefitinib resistance via activating Wnt/beta-catenin signal pathway in patients with non-small cell lung cancer. Clin Cancer Res. 2022;28(17):3770–84.
Han X, Jiang H, Qi J, Li J, Yang J, Tian Y, Li W, Jing Q, Wang C. Novel lncRNA UPLA1 mediates tumorigenesis and prognosis in lung adenocarcinoma. Cell Death Dis. 2020;11(11):999.
Yao Y, Zhou Y, Hua Q. circRNA hsa_circ_0018414 inhibits the progression of LUAD by sponging miR-6807-3p and upregulating DKK1. Mol Ther Nucleic Acids. 2021;23:783–96.
Li Y, Sheng H, Ma F, Wu Q, Huang J, Chen Q, Sheng L, Zhu X, Zhu X, Xu M. RNA m(6)A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/beta-catenin signaling. Cell Death Dis. 2021;12(5):479.
Sankar K, Gadgeel SM, Qin A. Molecular therapeutic targets in non-small cell lung cancer. Expert Rev Anticancer Ther. 2020;20(8):647–61.
Liu WJ, Du Y, Wen R, Yang M, Xu J. Drug resistance to targeted therapeutic strategies in non-small cell lung cancer. Pharmacol Ther. 2020;206: 107438.
Xue W, Cai L, Li S, Hou Y, Wang YD, Yang D, Xia Y, Nie X. WNT ligands in non-small cell lung cancer: from pathogenesis to clinical practice. Discov Oncol. 2023;14(1):136.
Sumitomo R, Huang CL, Ando H, Ishida T, Cho H, Date H. Wnt2b and Wnt5a expression is highly associated with M2 TAMs in non-small cell lung cancer. Oncol Rep. 2022;48(5):189.
Xu J, Lv W, Hu Y, Wang L, Wang Y, Cao J, Hu J. Wnt3a expression is associated with epithelial-mesenchymal transition and impacts prognosis of lung adenocarcinoma patients. J Cancer. 2017;8(13):2523–31.
Zhou HM, Zhao LM. Wnt signaling pathway-derived score for predicting therapeutic resistance and tumor microenvironment in lung adenocarcinoma. Front Pharmacol. 2022;13:1091018.
Li XS, Nie KC, Zheng ZH, Zhou RS, Huang YS, Ye ZJ, He F, Tang Y. Molecular subtypes based on DNA methylation predict prognosis in lung squamous cell carcinoma. BMC Cancer. 2021;21(1):96.
Coscio A, Chang DW, Roth JA, Ye Y, Gu J, Yang P, Wu X. Genetic variants of the Wnt signaling pathway as predictors of recurrence and survival in early-stage non-small cell lung cancer patients. Carcinogenesis. 2014;35(6):1284–91.
Wang HQ, Xu ML, Ma J, Zhang Y, Xie CH. Frizzled-8 as a putative therapeutic target in human lung cancer. Biochem Biophys Res Commun. 2012;417(1):62–6.
Lee EH, Chari R, Lam A, Ng RT, Yee J, English J, Evans KG, Macaulay C, Lam S, Lam WL. Disruption of the non-canonical WNT pathway in lung squamous cell carcinoma. Clin Med Oncol. 2008;2008(2):169–79.
Wang Y, Zhang Y, Fang M, Bao W, Deng D. Two novel susceptibility loci for non-small cell lung cancer map to low-density lipoprotein receptor-related protein 5. Oncol Lett. 2016;12(4):2307–18.
Deng D, Zhang Y, Bao W, Kong X. Low-density lipoprotein receptor-related protein 6 (LRP6) rs10845498 polymorphism is associated with a decreased risk of non-small cell lung cancer. Int J Med Sci. 2014;11(7):685–90.
Kafka A, Tomas D, Beros V, Pecina HI, Zeljko M, Pecina-Slaus N. Brain metastases from lung cancer show increased expression of DVL1, DVL3 and beta-catenin and down-regulation of E-cadherin. Int J Mol Sci. 2014;15(6):10635–51.
Zhao H, Wang Z, Wu G, Lu Y, Zheng J, Zhao Y, Han Y, Wang J, Yang L, Du J, et al. Role of MicroRNA-214 in dishevelled1-modulated beta-catenin signalling in non-small cell lung cancer progression. J Cancer. 2023;14(2):239–49.
Yang LH, Han Y, Li G, Xu HT, Jiang GY, Miao Y, Zhang XP, Zhao HY, Xu ZF, Stoecker M, et al. Axin gene methylation status correlates with radiosensitivity of lung cancer cells. BMC Cancer. 2013;13:368.
Yang LH, Xu HT, Li QC, Jiang GY, Zhang XP, Zhao HY, Xu K, Wang EH. Abnormal hypermethylation and clinicopathological significance of Axin gene in lung cancer. Tumour Biol. 2013;34(2):749–57.
Zhu L, Yang S, Zheng L, Zhang G, Cheng G. WNT/beta-catenin pathway activation via Wnt1 overexpression and Axin1 downregulation correlates with cadherin-catenin complex disruption and increased lymph node involvement in micropapillary-predominant lung adenocarcinoma. J Thorac Dis. 2020;12(10):5906–15.
Bahl C, Singh N, Behera D, Sharma S. Genetic variants in the wingless antagonist genes (sFRP, DKK, and Axin2) predict the overall survival and prognosis of north indian lung cancer patients treated with platinum-based doublet chemotherapy. Cancer Biother Radiopharm. 2018;33(10):466–77.
Bahl C, Sharma S, Singh N, Behera D. Association study between genetic variations in Axin2 gene and lung cancer risk in North Indian population: a multiple interaction analysis. Tumour Biol. 2017;39(4):1010428317695533.
Xu B, Yuan W, Shi L, Zuo L, Wu XY, Zhang W, Wen Q. New insights into the association between AXIN2 148 C/T, 1365 C/T, and rs4791171 A/G variants and cancer risk. Cancer Cell Int. 2019;19:119.
Liu D, Li L, Yang Y, Liu W, Wu J. The Axin2 rs2240308 polymorphism and susceptibility to lung cancer in a Chinese population. Tumour Biol. 2014;35(11):10987–91.
Paschidis K, Zougros A, Chatziandreou I, Tsikalakis S, Korkolopoulou P, Kavantzas N, Saetta AA. Methylation analysis of APC, AXIN2, DACT1, RASSF1A and MGMT gene promoters in non-small cell lung cancer. Pathol Res Pract. 2022;234: 153899.
Wang Z, Liu H, Liu B, Ma W, Xue X, Chen J, Zhou Q. Gene expression levels of CSNK1A1 and AAC-11, but not NME1, in tumor tissues as prognostic factors in NSCLC patients. Med Sci Monit. 2010;16(8):CR357-364.
Xu Y, Yu Y, Yan R, Ke X, Qu Y. Modulating beta-catenin homeostasis for cancer therapy. Trends Cancer. 2024.
Hu Y, Mu H, Yang Y. Histone demethylase PHF8 promotes cell growth and metastasis of non-small-cell lung cancer through activating Wnt/beta-catenin signaling pathway. Histol Histopathol. 2021;36(8):869–77.
Wu Q, Luo X, Terp MG, Li Q, Li Y, Shen L, Chen Y, Jacobsen K, Bivona TG, Chen H, et al. DDX56 modulates post-transcriptional Wnt signaling through miRNAs and is associated with early recurrence in squamous cell lung carcinoma. Mol Cancer. 2021;20(1):108.
Wu Y, Cheng K, Liang W, Wang X. lncRNA RPPH1 promotes non-small cell lung cancer progression through the miR-326/WNT2B axis. Oncol Lett. 2020;20(4):105.
Ma X, Chen Z, Chen W, Chen Z, Shang Y, Zhao Y, Li L, Zhou C, He J, Meng X. LncRNA AL139294.1 can be transported by extracellular vesicles to promote the oncogenic behaviour of recipient cells through activation of the Wnt and NF-kappaB2 pathways in non-small-cell lung cancer. J Exp Clin Cancer Res. 2024;43(1):20.
Luo J, Yao Y, Ji S, Sun Q, Xu Y, Liu K, Diao Q, Qiang Y, Shen Y. PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/beta-catenin signaling pathway. Cancer Cell Int. 2019;19:96.
Xia C, Xu X, Ding Y, Yu C, Qiao J, Liu P. Abnormal spindle-like microcephaly-associated protein enhances cell invasion through Wnt/beta-catenin-dependent regulation of epithelial-mesenchymal transition in non-small cell lung cancer cells. J Thorac Dis. 2021;13(4):2460–74.
Song JW, Zhu J, Wu XX, Tu T, Huang JQ, Chen GZ, Liang LY, Zhou CH, Xu X, Gong LY. GOLPH3/CKAP4 promotes metastasis and tumorigenicity by enhancing the secretion of exosomal WNT3A in non-small-cell lung cancer. Cell Death Dis. 2021;12(11):976.
Shang B, Lu F, Jiang S, Xing M, Mao X, Yang G, Zhang H. ALDOC promotes non-small cell lung cancer through affecting MYC-mediated UBE2N transcription and regulating Wnt/beta-catenin pathway. Aging (Albany NY). 2023;15(18):9614–32.
She K, Yang W, Li M, Xiong W, Zhou M. FAIM2 promotes non-small cell lung cancer cell growth and bone metastasis by activating the Wnt/beta-catenin pathway. Front Oncol. 2021;11: 690142.
Ma W, Wang C, Li R, Han Z, Jiang Y, Zhang X, Divisi D, Capobianco E, Zhang L, Dong W. PTS is activated by ATF4 and promotes lung adenocarcinoma development via the Wnt pathway. Transl Lung Cancer Res. 2022;11(9):1912–25.
Zhao Y, Dai Q, Fu X, Chen Q, Tang Y, Gao X, Zhou Q. CircVAPA exerts oncogenic property in non-small cell lung cancer by the miR-876-5p/WNT5A axis. J Gene Med. 2021;23(6): e3325.
Li H, Tong F, Meng R, Peng L, Wang J, Zhang R, Dong X. E2F1-mediated repression of WNT5A expression promotes brain metastasis dependent on the ERK1/2 pathway in EGFR-mutant non-small cell lung cancer. Cell Mol Life Sci. 2021;78(6):2877–91.
Du J, Liu H, Mao X, Qin Y, Fan C. ATF4 promotes lung cancer cell proliferation and invasion partially through regulating Wnt/beta-catenin signaling. Int J Med Sci. 2021;18(6):1442–8.
Wang R, Wang X, Zhang J, Liu Y. LINC00942 promotes tumor proliferation and metastasis in lung adenocarcinoma via FZD1 upregulation. Technol Cancer Res Treat. 2021;20:1533033820977526.
Yang B, Zhang B, Qi Q, Wang C. CircRNA has_circ_0017109 promotes lung tumor progression via activation of Wnt/beta-catenin signaling due to modulating miR-671-5p/FZD4 axis. BMC Pulm Med. 2022;22(1):443.
Ren Q, Chen J, Liu Y. LRP5 and LRP6 in Wnt signaling: similarity and divergence. Front Cell Dev Biol. 2021;9: 670960.
Li ZH, Lei L, Fei LR, Huang WJ, Zheng YW, Yang MQ, Wang Z, Liu CC, Xu HT. TRIP13 promotes the proliferation and invasion of lung cancer cells via the Wnt signaling pathway and epithelial-mesenchymal transition. J Mol Histol. 2021;52(1):11–20.
Hyun SY, Min HY, Lee HJ, Cho J, Boo HJ, Noh M, Jang HJ, Lee HJ, Park CS, Park JS, et al. Ninjurin1 drives lung tumor formation and progression by potentiating Wnt/beta-Catenin signaling through Frizzled2-LRP6 assembly. J Exp Clin Cancer Res. 2022;41(1):133.
Hong CL, Yu IS, Pai CH, Chen JS, Hsieh MS, Wu HL, Lin SW, Huang HP. CD248 regulates Wnt signaling in pericytes to promote angiogenesis and tumor growth in lung cancer. Cancer Res. 2022;82(20):3734–50.
Ng VH, Spencer Z, Neitzel LR, Nayak A, Loberg MA, Shen C, Kassel SN, Kroh HK, An Z, Anthony CC, et al. The USP46 complex deubiquitylates LRP6 to promote Wnt/beta-catenin signaling. Nat Commun. 2023;14(1):6173.
Song Z, Wang H, Zhang S. Negative regulators of Wnt signaling in non-small cell lung cancer: theoretical basis and therapeutic potency. Biomed Pharmacother. 2019;118: 109336.
Li H, Yang T, Shang D, Sun Z. miR-1254 promotes lung cancer cell proliferation by targeting SFRP1. Biomed Pharmacother. 2017;92:913–8.
Cho SH, Kuo IY, Lu PF, Tzeng HT, Lai WW, Su WC, Wang YC. Rab37 mediates exocytosis of secreted frizzled-related protein 1 to inhibit Wnt signaling and thus suppress lung cancer stemness. Cell Death Dis. 2018;9(9):868.
Xia Y, Wei K, Hu LQ, Zhou CR, Lu ZB, Zhan GS, Pan XL, Pan CF, Wang J, Wen W, et al. Exosome-mediated transfer of miR-1260b promotes cell invasion through Wnt/beta-catenin signaling pathway in lung adenocarcinoma. J Cell Physiol. 2020;235(10):6843–53.
Deng X, Qing Y, Horne D, Huang H, Chen J. The roles and implications of RNA m(6)A modification in cancer. Nat Rev Clin Oncol. 2023;20(8):507–26.
Rong L, Xu Y, Zhang K, Jin L, Liu X. HNRNPA2B1 inhibited SFRP2 and activated Wnt-beta/catenin via m6A-mediated miR-106b-5p processing to aggravate stemness in lung adenocarcinoma. Pathol Res Pract. 2022;233: 153794.
Zhao S, Song P, Zhou G, Zhang D, Hu Y. METTL3 promotes the malignancy of non-small cell lung cancer by N6-methyladenosine modifying SFRP2. Cancer Gene Ther. 2023;30(8):1094–104.
Ren W, Li Y, Chen X, Hu S, Cheng W, Cao Y, Gao J, Chen X, Xiong D, Li H, et al. RYR2 mutation in non-small cell lung cancer prolongs survival via down-regulation of DKK1 and up-regulation of GS1–115G20.1: a weighted gene Co-expression network analysis and risk prognostic models. IET Syst Biol. 2022;16(2):43–58.
Yang J, Liu Y, Mai X, Lu S, Jin L, Tai X. STAT1-induced upregulation of LINC00467 promotes the proliferation migration of lung adenocarcinoma cells by epigenetically silencing DKK1 to activate Wnt/beta-catenin signaling pathway. Biochem Biophys Res Commun. 2019;514(1):118–26.
Wang DP, Gu LL, Xue Q, Chen H, Mao GX. CtBP2 promotes proliferation and reduces drug sensitivity in non-small cell lung cancer via the Wnt/beta-catenin pathway. Neoplasma. 2018;65(6):888–97.
Zhang X, Yu X, Jiang G, Miao Y, Wang L, Zhang Y, Liu Y, Fan C, Lin X, Dong Q, et al. Cytosolic TMEM88 promotes invasion and metastasis in lung cancer cells by binding DVLS. Cancer Res. 2015;75(21):4527–37.
Wei L, Li P, Luo Y, Zhang M, Yan T, Yang Y, Han Y, Liu S, Wang E. PWP1 promotes the malignant phenotypes of lung cancer cells by interacting with DVL2 and merlin. Onco Targets Ther. 2020;13:10025–37.
Guan H, Zhu T, Wu S, Liu S, Liu B, Wu J, Cai J, Zhu X, Zhang X, Zeng M, et al. Long noncoding RNA LINC00673-v4 promotes aggressiveness of lung adenocarcinoma via activating WNT/beta-catenin signaling. Proc Natl Acad Sci U S A. 2019;116(28):14019–28.
Liu C, Liu L, Zhang Y, Jing H. Molecular mechanism of AQP3 in regulating differentiation and apoptosis of lung cancer stem cells through Wnt/GSK-3beta/beta-catenin pathway. J BUON. 2020;25(4):1714–20.
Zhu J, Wang S, Chen Y, Li X, Jiang Y, Yang X, Li Y, Wang X, Meng Y, Zhu M, et al. miR-19 targeting of GSK3beta mediates sulforaphane suppression of lung cancer stem cells. J Nutr Biochem. 2017;44:80–91.
Yang F, Xiong H, Duan L, Li Q, Li X, Zhou Y. MiR-1246 promotes metastasis and invasion of A549 cells by targeting GSK-3beta-mediated Wnt/beta-catenin pathway. Cancer Res Treat. 2019;51(4):1420–9.
Jiang N, Zou C, Zhu Y, Luo Y, Chen L, Lei Y, Tang K, Sun Y, Zhang W, Li S, et al. HIF-1a-regulated miR-1275 maintains stem cell-like phenotypes and promotes the progression of LUAD by simultaneously activating Wnt/beta-catenin and Notch signaling. Theranostics. 2020;10(6):2553–70.
Fang L, Cai J, Chen B, Wu S, Li R, Xu X, Yang Y, Guan H, Zhu X, Zhang L, et al. Aberrantly expressed miR-582-3p maintains lung cancer stem cell-like traits by activating Wnt/beta-catenin signalling. Nat Commun. 2015;6:8640.
Pan J, Fang S, Tian H, Zhou C, Zhao X, Tian H, He J, Shen W, Meng X, Jin X, et al. lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/beta-catenin signaling. Mol Cancer. 2020;19(1):9.
Lei L, Wang Y, Li ZH, Fei LR, Huang WJ, Zheng YW, Liu CC, Yang MQ, Wang Z, Zou ZF, et al. PHLDA3 promotes lung adenocarcinoma cell proliferation and invasion via activation of the Wnt signaling pathway. Lab Invest. 2021;101(9):1130–41.
Gu J, Zhang X, Jiang G, Li Q, Wang E, Yu J. ARHGEF40 promotes non-small cell lung cancer proliferation and invasion via the AKT-Wnt axis by binding to RhoA. Mol Carcinog. 2022;61(11):1016–30.
Gavagan M, Jameson N, Zalatan JG. The Axin scaffold protects the kinase GSK3beta from cross-pathway inhibition. Elife. 2023; 12.
Shi X, Zhao Y, Fan C. Zbed3 promotes proliferation and invasion of lung cancer partly through regulating the function of Axin-Gsk3beta complex. J Cell Mol Med. 2019;23(2):1014–21.
Jie L, Cong L, Conghui W, Ying G. GTPBP2 positively regulates the invasion, migration and proliferation of non-small cell lung cancer. J Cancer. 2021;12(13):3819–26.
Peng L, Liu Y, Chen J, Cheng M, Wu Y, Chen M, Zhong Y, Shen D, Chen L, Ye X. APEX1 regulates alternative splicing of key tumorigenesis genes in non-small-cell lung cancer. BMC Med Genomics. 2022;15(1):147.
Mei Y, Liu YB, Cao S, Tian ZW, Zhou HH. RIF1 promotes tumor growth and cancer stem cell-like traits in NSCLC by protein phosphatase 1-mediated activation of Wnt/beta-catenin signaling. Cell Death Dis. 2018;9(10):942.
Xu X, Zhang Y, Wang M, Zhang X, Jiang W, Wu S, Ti X. A Peptide encoded by a long non-coding RNA DLX6-AS1 facilitates cell proliferation, migration, and invasion by activating the wnt/beta-catenin signaling pathway in non-small-cell lung cancer cell. Crit Rev Eukaryot Gene Expr. 2022;32(8):43–53.
Xu G, Zhang Z, Zhang L, Chen Y, Li N, Lv Y, Li Y, Xu X. miR-4326 promotes lung cancer cell proliferation through targeting tumor suppressor APC2. Mol Cell Biochem. 2018;443(1–2):151–7.
Lin Y, Gu Q, Sun Z, Sheng B, Qi C, Liu B, Fu T, Liu C, Zhang Y. Upregulation of miR-3607 promotes lung adenocarcinoma proliferation by suppressing APC expression. Biomed Pharmacother. 2017;95:497–503.
Cen W, Yan Q, Zhou W, Mao M, Huang Q, Lin Y, Jiang N. miR-4739 promotes epithelial-mesenchymal transition and angiogenesis in “driver gene-negative” non-small cell lung cancer via activating the Wnt/β-catenin signaling. Cell Oncol (Dordr). 2023;46(6):1821–35.
Wu XT, Wang YH, Cai XY, Dong Y, Cui Q, Zhou YN, Yang XW, Lu WF, Zhang M. RNF115 promotes lung adenocarcinoma through Wnt/beta-catenin pathway activation by mediating APC ubiquitination. Cancer Metab. 2021;9(1):7.
He Y, Jiang X, Duan L, Xiong Q, Yuan Y, Liu P, Jiang L, Shen Q, Zhao S, Yang C, et al. LncRNA PKMYT1AR promotes cancer stem cell maintenance in non-small cell lung cancer via activating Wnt signaling pathway. Mol Cancer. 2021;20(1):156.
Lin H, Shangguan Z, Zhu M, Bao L, Zhang Q, Pan S. lncRNA FLVCR1-AS1 silencing inhibits lung cancer cell proliferation, migration, and invasion by inhibiting the activity of the Wnt/beta-catenin signaling pathway. J Cell Biochem. 2019;120(6):10625–32.
Zhang Y, Liu H, Zhang Q, Zhang Z. Long noncoding RNA LINC01006 facilitates cell proliferation, migration, and epithelial-mesenchymal transition in lung adenocarcinoma via targeting the MicroRNA 129-2-3p/CTNNB1 axis and activating Wnt/beta-catenin signaling pathway. Mol Cell Biol. 2021;41(6): e0038020.
Liu S, Yang N, Wang L, Wei B, Chen J, Gao Y. lncRNA SNHG11 promotes lung cancer cell proliferation and migration via activation of Wnt/beta-catenin signaling pathway. J Cell Physiol. 2020;235(10):7541–53.
Xu Q, Wang C, Zhou JX, Xu ZM, Gao J, Sui P, Walsh CP, Ji H, Xu GL. Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development. Proc Natl Acad Sci U S A. 2022;119(6): e2107599119.
Zheng JY, Zhu T, Zhuo W, Mao XY, Yin JY, Li X, He YJ, Zhang W, Liu C, Liu ZQ. eIF3a sustains non-small cell lung cancer stem cell-like properties by promoting YY1-mediated transcriptional activation of beta-catenin. Biochem Pharmacol. 2023;213: 115616.
Wei X, Liao J, Lei Y, Li M, Zhao G, Zhou Y, Ye L, Huang Y. WSB2 as a target of Hedgehog signaling promoted the malignant biological behavior of Xuanwei lung cancer through regulating Wnt/beta-catenin signaling. Transl Cancer Res. 2020;9(12):7394–404.
Liao Y, Feng J, Sun W, Wu C, Li J, Jing T, Liang Y, Qian Y, Liu W, Wang H. CIRP promotes the progression of non-small cell lung cancer through activation of Wnt/beta-catenin signaling via CTNNB1. J Exp Clin Cancer Res. 2021;40(1):275.
Qi W, Chen J, Cheng X, Huang J, Xiang T, Li Q, Long H, Zhu B. Targeting the Wnt-regulatory protein CTNNBIP1 by microRNA-214 enhances the stemness and self-renewal of cancer stem-like cells in lung adenocarcinomas. Stem Cells. 2015;33(12):3423–36.
Zhang X, Zhang Y, Wang C, Wang X. TET (Ten-eleven translocation) family proteins: structure, biological functions and applications. Signal Transduct Target Ther. 2023;8(1):297.
Zhu Y, Wu H, Yang X, Xiong Z, Zhao T, Gan X. LINC00514 facilitates cell proliferation, migration, invasion, and epithelial-mesenchymal transition in non-small cell lung cancer by acting on the Wnt/beta-catenin signaling pathway. Bioengineered. 2022;13(5):13654–66.
Chang R, Xiao X, Fu Y, Zhang C, Zhu X, Gao Y. ITGB1-DT facilitates lung adenocarcinoma progression via forming a positive feedback loop with ITGB1/Wnt/beta-catenin/MYC. Front Cell Dev Biol. 2021;9: 631259.
Zhang C, Huang J, Lou K, Ouyang H. Long noncoding RNASEH1-AS1 exacerbates the progression of non-small cell lung cancer by acting as a ceRNA to regulate microRNA-516a-5p/FOXK1 and thereby activating the Wnt/beta-catenin signaling pathway. Cancer Med. 2022;11(7):1589–604.
Chen T, Feng G, Xing Z, Gao X. Circ-EIF3I facilitates proliferation, migration, and invasion of lung cancer via regulating the activity of Wnt/beta-catenin pathway through the miR-1253/NOVA2 axis. Thorac Cancer. 2022;13(22):3133–44.
Fan Z, Wang H. CircZSWIM4 facilitates tumor development in lung adenocarcinoma by targeting miR-370-3p and miR-873-5p to regulate the axis of FOXM1/beta-catenin. Cell Mol Biol (Noisy-le-grand). 2023;69(6):132–40.
Zhang X, Yin Z, Li C, Nie L, Chen K. KDM2B mediates the Wnt/beta-catenin pathway through transcriptional activation of PKMYT1 via microRNA-let-7b-5p/EZH2 to affect the development of non-small cell lung cancer. Exp Cell Res. 2022;417(2): 113208.
Wang R, Liu J, Li K, Yang G, Chen S, Wu J, Xie X, Ren H, Pang Y. An SETD1A/Wnt/beta-catenin feedback loop promotes NSCLC development. J Exp Clin Cancer Res. 2021;40(1):318.
Huang J, Tian F, Song Y, Cao M, Yan S, Lan X, Cui Y, Cui Y, Cui Y, Jia D, et al. A feedback circuit comprising EHD1 and 14-3-3zeta sustains beta-catenin/c-Myc-mediated aerobic glycolysis and proliferation in non-small cell lung cancer. Cancer Lett. 2021;520:12–25.
Liu S, Tian Y, Zheng Y, Cheng Y, Zhang D, Jiang J, Li S. TRIM27 acts as an oncogene and regulates cell proliferation and metastasis in non-small cell lung cancer through SIX3-beta-catenin signaling. Aging (Albany NY). 2020;12(24):25564–80.
Liu K, Cheng L, Zhu K, Wang J, Shu Q. The cancer/testis antigen HORMAD1 mediates epithelial-mesenchymal transition to promote tumor growth and metastasis by activating the Wnt/beta-catenin signaling pathway in lung cancer. Cell Death Discov. 2022;8(1):136.
Yang L, Chen Y, Cui T, Knosel T, Zhang Q, Albring KF, Huber O, Petersen I. Desmoplakin acts as a tumor suppressor by inhibition of the Wnt/beta-catenin signaling pathway in human lung cancer. Carcinogenesis. 2012;33(10):1863–70.
Huang J, Lan X, Wang T, Lu H, Cao M, Yan S, Cui Y, Jia D, Cai L, Xing Y. Targeting the IL-1beta/EHD1/TUBB3 axis overcomes resistance to EGFR-TKI in NSCLC. Oncogene. 2020;39(8):1739–55.
Bai Q, Yang X, Li Q, Chen W, Tian H, Lian R, Liu X, Wang S, Yang Y. Metastatic tumor cell-specific FABP7 promotes NSCLC metastasis via inhibiting β-catenin degradation. Cells. 2022;11(5):805.
Tung CH, Wu JE, Huang MF, Wang WL, Wu YY, Tsai YT, Hsu XR, Lin SH, Chen YL, Hong TM. Ubiquitin-specific peptidase 5 facilitates cancer stem cell-like properties in lung cancer by deubiquitinating beta-catenin. Cancer Cell Int. 2023;23(1):207.
Zhang J, Zhang X, Yang S, Bao Y, Xu D, Liu L. FOXH1 promotes lung cancer progression by activating the Wnt/beta-catenin signaling pathway. Cancer Cell Int. 2021;21(1):293.
Fang Z, Zhong M, Zhou L, Le Y, Wang H, Fang Z. Low-density lipoprotein receptor-related protein 8 facilitates the proliferation and invasion of non-small cell lung cancer cells by regulating the Wnt/beta-catenin signaling pathway. Bioengineered. 2022;13(3):6807–18.
Wang Z, Fang Z, Chen G, Liu B, Xu J, Li F, Li F, Liu H, Zhang H, Sun Y, et al. Chromobox 4 facilitates tumorigenesis of lung adenocarcinoma through the Wnt/beta-catenin pathway. Neoplasia. 2021;23(2):222–33.
Chen D, Gao S, Gao F, Liu A, Li J, Li J, Liu Q. SMEK1 promotes lung adenocarcinoma proliferation and invasion by activating Wnt/beta-catenin signaling pathway. Clin Transl Oncol. 2023;25(4):976–86.
Wu Q, Li R, Wang QX, Zhang MY, Liu TT, Qu YQ. Junctional adhesion molecule-like protein promotes tumor progression via the Wnt/beta-catenin signaling pathway in lung adenocarcinoma. J Transl Med. 2022;20(1):260.
Huang X, Jiang L, Lu S, Yuan M, Lin H, Li B, Wen Z, Zhong Y. Overexpression of ERCC6L correlates with poor prognosis and confers malignant phenotypes of lung adenocarcinoma. Oncol Rep. 2022;48(1):131.
Qu L, Tian Y, Wang F, Li Z. NOVA1 promotes NSCLC proliferation and invasion by activating Wnt/beta-catenin signaling. BMC Cancer. 2022;22(1):1091.
Sun QY, Ding LW, Xiao JF, Chien W, Lim SL, Hattori N, Goodglick L, Chia D, Mah V, Alavi M, et al. SETDB1 accelerates tumourigenesis by regulating the WNT signalling pathway. J Pathol. 2015;235(4):559–70.
Wang XH, Zhang SY, Shi M, Xu XP. HMGB1 promotes the proliferation and metastasis of lung cancer by activating the Wnt/beta-catenin pathway. Technol Cancer Res Treat. 2020;19:1533033820948054.
Yang Y, Liu L, Cai J, Wu J, Guan H, Zhu X, Yuan J, Li M. DEPDC1B enhances migration and invasion of non-small cell lung cancer cells via activating Wnt/beta-catenin signaling. Biochem Biophys Res Commun. 2014;450(1):899–905.
Liu M, Sun X, Shi S. MORC2 enhances tumor growth by promoting angiogenesis and tumor-associated macrophage recruitment via Wnt/beta-catenin in lung cancer. Cell Physiol Biochem. 2018;51(4):1679–94.
Chen W, Wu J, Wang W, Yu L, Xu X. PLAC8 overexpression promotes lung cancer cell growth via Wnt/beta-catenin signaling. J Immunol Res. 2022;2022:8854196.
Feng Y, Gao Y, Yu J, Jiang G, Zhang X, Lin X, Han Q, Rong X, Xu H, Li Q, et al. CCDC85B promotes non-small cell lung cancer cell proliferation and invasion. Mol Carcinog. 2019;58(1):126–34.
Chen N, Wu Q, Zhang G, Fu J, Geng Q, Zhang Y. Deactivation of AKT/GSK-3beta-mediated Wnt/beta-catenin pathway by silencing of KIF26B weakens the malignant behaviors of non-small cell lung cancer. Tissue Cell. 2022;76: 101750.
Zhang D, Sun L, Zhang J. TMED3 exerts a protumor function in non-small cell lung cancer by enhancing the Wnt/beta-catenin pathway via regulation of AKT. Toxicol Appl Pharmacol. 2021;433: 115793.
Ma Y, Marinkova R, Nenkov M, Jin L, Huber O, Sonnemann J, Peca N, Gaßler N, Chen Y. Tumor-intrinsic PD-L1 exerts an oncogenic function through the activation of the Wnt/β-catenin pathway in human non-small cell lung cancer. Int J Mol Sci. 2022;23(19):11031.
Hou S, Tian T, Qi D, Sun K, Yuan Q, Wang Z, Qin Z, Wu Z, Chen Z, Zhang J. S100A4 promotes lung tumor development through beta-catenin pathway-mediated autophagy inhibition. Cell Death Dis. 2018;9(3):277.
Hou M, Wu N, Yao L. LncRNA CBR3-AS1 potentiates Wnt/beta-catenin signaling to regulate lung adenocarcinoma cells proliferation, migration and invasion. Cancer Cell Int. 2021;21(1):36.
Zhu J, Cao K, Zhang P, Ma J. LINC00669 promotes lung adenocarcinoma growth by stimulating the Wnt/beta-catenin signaling pathway. Cancer Med. 2023;12(7):9005–23.
Ling B, Wei P, Xiao J, Cen B, Wei H, Feng X, Ye G, Li S, Zhang Z, Liang W, et al. Nucleolar and spindle-associated protein 1 promotes non-small cell lung cancer progression and serves as an effector of myocyte enhancer factor 2D. Oncol Rep. 2021;45(3):1044–58.
Cai DJ, Zhang ZY, Bu Y, Li L, Deng YZ, Sun LQ, Hu CP, Li M. Asparagine synthetase regulates lung-cancer metastasis by stabilizing the beta-catenin complex and modulating mitochondrial response. Cell Death Dis. 2022;13(6):566.
Gong L, Song J, Lin X, Wei F, Zhang C, Wang Z, Zhu J, Wu S, Chen Y, Liang J, et al. Serine-arginine protein kinase 1 promotes a cancer stem cell-like phenotype through activation of Wnt/beta-catenin signalling in NSCLC. J Pathol. 2016;240(2):184–96.
Zhou SY, Xu ML, Wang SQ, Zhang F, Wang L, Wang HQ. Overexpression of Pygopus-2 is required for canonical Wnt activation in human lung cancer. Oncol Lett. 2014;7(1):233–8.
Li Y, Chen F, Shen W, Li B, Xiang R, Qu L, Zhang C, Li G, Xie H, Katanaev VL, et al. WDR74 induces nuclear beta-catenin accumulation and activates Wnt-responsive genes to promote lung cancer growth and metastasis. Cancer Lett. 2020;471:103–15.
Zhang HJ, Chang WJ, Jia CY, Qiao L, Zhou J, Chen Q, Zheng XW, Zhang JH, Li HC, Yang ZY, et al. Destrin contributes to lung adenocarcinoma progression by activating Wnt/beta-catenin signaling pathway. Mol Cancer Res. 2020;18(12):1789–802.
Huang JQ, Wei FK, Xu XL, Ye SX, Song JW, Ding PK, Zhu J, Li HF, Luo XP, Gong H, et al. SOX9 drives the epithelial-mesenchymal transition in non-small-cell lung cancer through the Wnt/beta-catenin pathway. J Transl Med. 2019;17(1):143.
Su YJ, Chang YW, Lin WH, Liang CL, Lee JL. An aberrant nuclear localization of E-cadherin is a potent inhibitor of Wnt/beta-catenin-elicited promotion of the cancer stem cell phenotype. Oncogenesis. 2015;4(6): e157.
Wen Y, Li Y, Yang B, Guo X, Lin L, Liang J, Zhang K, Li X, Jiang Z, Wang Y, et al. Pygo1 regulates the behavior of human non-small-cell lung cancer via the Wnt/beta-catenin pathway. Dis Markers. 2022;2022:6993994.
Yang S, Liu Y, Li MY, Ng CSH, Yang SL, Wang S, Zou C, Dong Y, Du J, Long X, et al. FOXP3 promotes tumor growth and metastasis by activating Wnt/beta-catenin signaling pathway and EMT in non-small cell lung cancer. Mol Cancer. 2017;16(1):124.
Zhang X, Zhong N, Li X, Chen MB. TRIB3 promotes lung cancer progression by activating beta-catenin signaling. Eur J Pharmacol. 2019;863: 172697.
Gu B, Wang J, Song Y, Wang Q, Wu Q. microRNA-383 regulates cell viability and apoptosis by mediating Wnt/beta-catenin signaling pathway in non-small cell lung cancer. J Cell Biochem. 2019;120(5):7918–26.
Wang Y, Ha M, Li M, Zhang L, Chen Y. Histone deacetylase 6-mediated downregulation of TMEM100 expedites the development and progression of non-small cell lung cancer. Hum Cell. 2022;35(1):271–85.
Wang H, Chen X, Yang B, Xia Z, Chen Q. MiR-924 as a tumor suppressor inhibits non-small cell lung cancer by inhibiting RHBDD1/Wnt/beta-catenin signaling pathway. Cancer Cell Int. 2020;20:491.
Wang B, Sun L, Li J, Jiang R. miR-577 suppresses cell proliferation and epithelial-mesenchymal transition by regulating the WNT2B mediated Wnt/beta-catenin pathway in non-small cell lung cancer. Mol Med Rep. 2018;18(3):2753–61.
Li J, Lu R, Yang K, Sun Q. circCCT3 enhances invasion and epithelial-mesenchymal transition (EMT) of non-small-cell lung cancer (NSCLC) via the miR-107/Wnt/FGF7 axis. J Oncol. 2022;2022:7020774.
Yuan S, Yu Z, Liu Q, Zhang M, Xiang Y, Wu N, Wu L, Hu Z, Xu B, Cai T, et al. GPC5, a novel epigenetically silenced tumor suppressor, inhibits tumor growth by suppressing Wnt/beta-catenin signaling in lung adenocarcinoma. Oncogene. 2016;35(47):6120–31.
Liu J, Zhao ZX, Li BK, Zhao ZW. GRIK3 deficiency promotes non-small cell lung cancer progression by the regulation of the UBE2C/CDK1/Wnt signaling pathway. Am J Cancer Res. 2023;13(5):2066–75.
Zhao P, Zhao Q, Chen C, Lu S, Jin L. miR-4757-3p inhibited the migration and invasion of lung cancer cell via targeting Wnt signaling pathway. J Oncol. 2023;2023:6544042.
Liu M, Zhang Y, Zhang J, Cai H, Zhang C, Yang Z, Niu Y, Wang H, Wei X, Wang W, et al. MicroRNA-1253 suppresses cell proliferation and invasion of non-small-cell lung carcinoma by targeting WNT5A. Cell Death Dis. 2018;9(2):189.
Zhang Q, Fan H, Liu H, Jin J, Zhu S, Zhou L, Liu H, Zhang F, Zhan P, Lv T, et al. WNT5B exerts oncogenic effects and is negatively regulated by miR-5587-3p in lung adenocarcinoma progression. Oncogene. 2020;39(7):1484–97.
Yang Y, Sun Y, Wu Y, Tang D, Ding X, Xu W, Su B, Gao W. Downregulation of miR-3127-5p promotes epithelial-mesenchymal transition via FZD4 regulation of Wnt/beta-catenin signaling in non-small-cell lung cancer. Mol Carcinog. 2018;57(7):842–53.
Hsiao YJ, Chang WH, Chen HY, Hsu YC, Chiu SC, Chiang CC, Chang GC, Chen YJ, Wang CY, Chen YM, et al. MITF functions as a tumor suppressor in non-small cell lung cancer beyond the canonically oncogenic role. Aging (Albany NY). 2020;13(1):646–74.
Fu X, Li H, Liu C, Hu B, Li T, Wang Y. Long noncoding RNA AK126698 inhibits proliferation and migration of non-small cell lung cancer cells by targeting Frizzled-8 and suppressing Wnt/beta-catenin signaling pathway. Onco Targets Ther. 2016;9:3815–27.
Han X, Dong Q, Wu J, Luo Y, Rong X, Han Q, Zheng X, Wang E. RASSF10 suppresses lung cancer proliferation and invasion by decreasing the level of phosphorylated LRP6. Mol Carcinog. 2019;58(7):1168–80.
Li X, Lv F, Li F, Du M, Liang Y, Ju S, Liu Z, Zhou B, Wang B, Gao Y. LINC01089 inhibits tumorigenesis and epithelial-mesenchymal transition of non-small cell lung cancer via the miR-27a/SFRP1/Wnt/beta-catenin axis. Front Oncol. 2020;10: 532581.
Yu J, Ge Z, Chen S, Li S, Zhang X, Hu J, Guo W, Wang Y. miR-26a-5p suppresses Wnt/beta-catenin signaling pathway by inhibiting DNMT3A-mediated SFRP1 methylation and inhibits cancer stem cell-like properties of NSCLC. Dis Markers. 2022;2022:7926483.
Yao Y, Hua Q, Zhou Y. CircRNA has_circ_0006427 suppresses the progression of lung adenocarcinoma by regulating miR-6783-3p/DKK1 axis and inactivating Wnt/beta-catenin signaling pathway. Biochem Biophys Res Commun. 2019;508(1):37–45.
Zheng Y, Zhou Z, Wei R, Xiao C, Zhang H, Fan T, Zheng B, Li C, He J. The RNA-binding protein PCBP1 represses lung adenocarcinoma progression by stabilizing DKK1 mRNA and subsequently downregulating beta-catenin. J Transl Med. 2022;20(1):343.
Liu W, Fu X, Li R. CNN1 regulates the DKK1/Wnt/beta-catenin/c-myc signaling pathway by activating TIMP2 to inhibit the invasion, migration and EMT of lung squamous cell carcinoma cells. Exp Ther Med. 2021;22(2):855.
Zhang Y, Yuan J, Guo M, Xiang R, Xie T, Zhuang X, Dai W, Li Q, Lai Q. Upregulation of long intergenic non-coding RNA LINC00326 inhibits non-small cell lung carcinoma progression by blocking Wnt/beta-catenin pathway through modulating the miR-657/dickkopf WNT signaling pathway inhibitor 2 axis. Biol Direct. 2023;18(1):3.
Song W, Wu X, Cheng C, Li D, Chen J, Zhang W. ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/beta-catenin signaling pathway via suppressing DKK2. Genomics. 2023;115(5): 110684.
Han Q, Lin X, Zhang X, Jiang G, Zhang Y, Miao Y, Rong X, Zheng X, Han Y, Han X, et al. WWC3 regulates the Wnt and Hippo pathways via Dishevelled proteins and large tumour suppressor 1, to suppress lung cancer invasion and metastasis. J Pathol. 2017;242(4):435–47.
Zhu MC, Zhang YH, Xiong P, Fan XW, Li GL, Zhu M. Circ-GSK3B up-regulates GSK3B to suppress the progression of lung adenocarcinoma. Cancer Gene Ther. 2022;29(11):1761–72.
Cheng S, Qian F, Huang Q, Wei L, Fu Y, Du Y. HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells. Cell Death Dis. 2018;9(5):465.
Hubert KA, Wellik DM. Hox genes in development and beyond. Development. 2023; 150(1).
Shi XY, Tao XF, Wang GW, He JF, Wu LF, Sun YZ, Sun XJ. LncDBH-AS1 knockdown enhances proliferation of non-small cell lung cancer cells by activating the Wnt signaling pathway via the miR-155/AXIN1 axis. Eur Rev Med Pharmacol Sci. 2021;25(1):139–44.
Shen DJ, Jiang YH, Li JQ, Xu LW, Tao KY. The RNA-binding protein RBM47 inhibits non-small cell lung carcinoma metastasis through modulation of AXIN1 mRNA stability and Wnt/beta-catentin signaling. Surg Oncol. 2020;34:31–9.
Jian SF, Hsiao CC, Chen SY, Weng CC, Kuo TL, Wu DC, Hung WC, Cheng KH. Utilization of liquid chromatography mass spectrometry analyses to identify LKB1-APC interaction in modulating Wnt/beta-catenin pathway of lung cancer cells. Mol Cancer Res. 2014;12(4):622–35.
Wang F, Li S. Forkhead Box S1 inhibits the progression of lung squamous cell carcinoma cells by mediating Wnt/beta-catenin pathway. Chin J Physiol. 2022;65(5):266–75.
Zhou S, Qian K, Yu S, Zhao Y, Shen Q, Li Y. MiR-4429 alleviates malignant behaviors of lung adenocarcioma through Wnt/beta-catenin pathway. Cancer Biother Radiopharm. 2021.
Chen J, Wang D, Chen H, Gu J, Jiang X, Han F, Cao J, Liu W, Liu J. TMEM196 inhibits lung cancer metastasis by regulating the Wnt/beta-catenin signaling pathway. J Cancer Res Clin Oncol. 2023;149(2):653–67.
Han F, Zhang MQ, Liu WB, Sun L, Hao XL, Yin L, Jiang X, Cao J, Liu JY. SOX30 specially prevents Wnt-signaling to suppress metastasis and improve prognosis of lung adenocarcinoma patients. Respir Res. 2018;19(1):241.
Pribluda A, Daemen A, Lima AN, Wang X, Hafner M, Poon C, Modrusan Z, Katakam AK, Foreman O, Eastham J, et al. EHMT2 methyltransferase governs cell identity in the lung and is required for KRAS (G12D) tumor development and propagation. Elife. 2022;11: e57648.
Yang J, Han F, Liu W, Zhang M, Huang Y, Hao X, Jiang X, Yin L, Chen H, Cao J, et al. LHX6, an independent prognostic factor, inhibits lung adenocarcinoma progression through transcriptional silencing of beta-catenin. J Cancer. 2017;8(13):2561–74.
Lu J, Du C, Yao J, Wu B, Duan Y, Zhou L, Xu D, Zhou F, Gu L, Zhou H, et al. C/EBPalpha suppresses lung adenocarcinoma cell invasion and migration by inhibiting beta-catenin. Cell Physiol Biochem. 2017;42(5):1779–88.
Xu K, Liu B, Ma Y. The tumor suppressive roles of ARHGAP25 in lung cancer cells. Onco Targets Ther. 2019;12:6699–710.
Yang Y, Li Z, Yuan H, Ji W, Wang K, Lu T, Yu Y, Zeng Q, Li F, Xia W, et al. Reciprocal regulatory mechanism between miR-214-3p and FGFR1 in FGFR1-amplified lung cancer. Oncogenesis. 2019;8(9):50.
Xie Y, Xue C, Guo S, Yang L. MicroRNA-520a suppresses pathogenesis and progression of non-small-cell lung cancer through targeting the RRM2/Wnt axis. Anal Cell Pathol (Amst). 2021;2021:9652420.
Lai W, Yue Y, Zeng G. MicroRNA-34c-5p reduces malignant properties of lung cancer cells through regulation of TBL1XR1/Wnt/β-catenin signaling. Curr Mol Med. 2024;24(1):114–22.
Hao X, Su A. MiR-590 suppresses the progression of non-small cell lung cancer by regulating YAP1 and Wnt/beta-catenin signaling. Clin Transl Oncol. 2022;24(3):546–55.
Wan L, Zhang L, Fan K, Cheng ZX, Sun QC, Wang JJ. Circular RNA-ITCH suppresses lung cancer proliferation via inhibiting the Wnt/beta-catenin pathway. Biomed Res Int. 2016;2016:1579490.
Gao F, Jia L, Han J, Wang Y, Luo W, Zeng Y. Circ-ZNF124 downregulation inhibits non-small cell lung cancer progression partly by inactivating the Wnt/beta-catenin signaling pathway via mediating the miR-498/YES1 axis. Anticancer Drugs. 2021;32(3):257–68.
Zhong C, Chen M, Chen Y, Yao F, Fang W. Loss of DSTYK activates Wnt/beta-catenin signaling and glycolysis in lung adenocarcinoma. Cell Death Dis. 2021;12(12):1122.
Yuan J, Xing H, Li Y, Song Y, Zhang N, Xie M, Liu J, Xu Y, Shen Y, Wang B, et al. EPB41 suppresses the Wnt/beta-catenin signaling in non-small cell lung cancer by sponging ALDOC. Cancer Lett. 2021;499:255–64.
Luo Z, Ye X, Cheng Y, Li F, Shou F, Wang G. E3 ubiquitin ligase PJA1 regulates lung adenocarcinoma apoptosis and invasion through promoting FOXR2 degradation. Biochem Biophys Res Commun. 2021;556:106–13.
Zhan W, Li Y, Liu X, Zheng C, Fu Y. ZNF671 inhibits the proliferation and metastasis of NSCLC via the Wnt/beta-catenin pathway. Cancer Manag Res. 2020;12:599–610.
Zhang P, Li L, Wang B, Ran X, Yang S, Luo Y, Li Y, Wang Z, Liu Y, Zhu B. miR-489-3p promotes malignant progression of non-small cell lung cancer through the inactivation of Wnt/beta-catenin signaling pathway via regulating USP48. Respir Res. 2022;23(1):93.
Chen CC, Chen HY, Su KY, Hong QS, Yan BS, Chen CH, Pan SH, Chang YL, Wang CJ, Hung PF, et al. Shisa3 is associated with prolonged survival through promoting beta-catenin degradation in lung cancer. Am J Respir Crit Care Med. 2014;190(4):433–44.
Liu XL, Meng J, Zhang XT, Liang XH, Zhang F, Zhao GR, Zhang T. ING5 inhibits lung cancer invasion and epithelial-mesenchymal transition by inhibiting the WNT/beta-catenin pathway. Thorac Cancer. 2019;10(4):848–55.
Ning Q, Pang Y, Shao S, Luo M, Zhao L, Hu T, Zhao X. MicroRNA-147b suppresses the proliferation and invasion of non-small-cell lung cancer cells through downregulation of Wnt/beta-catenin signalling via targeting of RPS15A. Clin Exp Pharmacol Physiol. 2020;47(3):449–58.
Kong W, Chen Y, Zhao Z, Zhang L, Lin X, Luo X, Wang S, Song Z, Lin X, Lai G, et al. EXT1 methylation promotes proliferation and migration and predicts the clinical outcome of non-small cell lung carcinoma via WNT signalling pathway. J Cell Mol Med. 2021;25(5):2609–20.
Yang M, Han YM, Han Q, Rong XZ, Liu XF, Ln XY. KCTD11 inhibits progression of lung cancer by binding to beta-catenin to regulate the activity of the Wnt and Hippo pathways. J Cell Mol Med. 2021;25(19):9411–26.
Chen X, Meng J, Yue W, Yu J, Yang J, Yao Z, Zhang L. Fibulin-3 suppresses Wnt/beta-catenin signaling and lung cancer invasion. Carcinogenesis. 2014;35(8):1707–16.
Li S, Qi S, Li Y, Zhang C, Sun L, Liu C, Wang H. MARVELD3 inhibits the epithelial-mesenchymal transition and cell migration by suppressing the Wnt/beta-catenin signaling pathway in non-small cell lung cancer cells. Thorac Cancer. 2023;14(12):1045–58.
Cao Y, Geng J, Wang X, Meng Q, Xu S, Lang Y, Zhou Y, Qi L, Wang Z, Wei Z, et al. RNA-binding motif protein 10 represses tumor progression through the Wnt/beta- catenin pathway in lung adenocarcinoma. Int J Biol Sci. 2022;18(1):124–39.
Han F, Liu WB, Shi XY, Yang JT, Zhang X, Li ZM, Jiang X, Yin L, Li JJ, Huang CS, et al. SOX30 inhibits tumor metastasis through attenuating Wnt-signaling via transcriptional and posttranslational regulation of beta-catenin in lung cancer. EBioMedicine. 2018;31:253–66.
Wang Y, Wang L, Guo J, Zuo S, Wang Z, Hua S. MYPT1, regulated by miR-19b-3p inhibits the progression of non-small cell lung cancer via inhibiting the activation of wnt/beta-catenin signaling. Life Sci. 2021;278: 119573.
Hao X, Han F, Ma B, Zhang N, Chen H, Jiang X, Yin L, Liu W, Ao L, Cao J, et al. SOX30 is a key regulator of desmosomal gene suppressing tumor growth and metastasis in lung adenocarcinoma. J Exp Clin Cancer Res. 2018;37(1):111.
Ye L, Xiang T, Zhu J, Li D, Shao Q, Peng W, Tang J, Li L, Ren G. Interferon consensus sequence-binding protein 8, a tumor suppressor, suppresses tumor growth and invasion of non-small cell lung cancer by interacting with the Wnt/beta-catenin pathway. Cell Physiol Biochem. 2018;51(2):961–78.
Zhu J, Wang Y, Duan J, Bai H, Wang Z, Wei L, Zhao J, Zhuo M, Wang S, Yang L, et al. DNA Methylation status of Wnt antagonist SFRP5 can predict the response to the EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer. J Exp Clin Cancer Res. 2012;31(1):80.
Shen Z, Chen C, Sun J, Huang J, Liu S. The status of WIF1 methylation in cell-free DNA is associated with the insusceptibility for gefitinib in the treatment of lung cancer. J Cancer Res Clin Oncol. 2021;147(8):2239–48.
Cheng L, Tong Q. Interaction of FLNA and ANXA2 promotes gefitinib resistance by activating the Wnt pathway in non-small-cell lung cancer. Mol Cell Biochem. 2021;476(10):3563–75.
Yan R, Fan X, Xiao Z, Liu H, Huang X, Liu J, Zhang S, Yao J, An G, Ge Y. Inhibition of DCLK1 sensitizes resistant lung adenocarcinomas to EGFR-TKI through suppression of Wnt/beta-Catenin activity and cancer stemness. Cancer Lett. 2022;531:83–97.
Wang Q, Liao J, He Z, Su Y, Lin D, Xu L, Xu H, Lin J. LHX6 affects erlotinib resistance and migration of EGFR-mutant non-small-cell lung cancer HCC827 cells through suppressing Wnt/beta-catenin signaling. Onco Targets Ther. 2020;13:10983–94.
Nie M, Chen N, Pang H, Jiang T, Jiang W, Tian P, Yao L, Chen Y, DeBerardinis RJ, Li W, et al. Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse. J Clin Invest. 2022;132(20): e160152.
Li K, Peng ZY, Wang R, Li X, Du N, Liu DP, Zhang J, Zhang YF, Ma L, Sun Y, et al. Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7. Mol Cancer. 2023;22(1):103.
Ouseph MM, Taber A, Khurshid H, Madison R, Aswad BI, Resnick MB, Yakirevich E, Ali SM, Patel NR. TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations. Lung Cancer (Auckl). 2019;10:81–6.
Riely GJ, Wood DE, Ettinger DS, Aisner DL, Akerley W, Bauman JR, Bharat A, Bruno DS, Chang JY, Chirieac LR, et al. Non-small cell lung cancer, version 4.2024. J Natl Compr Canc Netw. 2024;22(4):249–74.
Oncology Society of Chinese Medical A, Chinese Medical Association Publishing H. Oncology Society of Chinese Medical Association guideline for clinical diagnosis and treatment of lung cancer (2021 edition). Zhonghua Zhong Liu Za Zhi. 2021;43(6):591–621.
Luo K, Gu X, Liu J, Zeng G, Peng L, Huang H, Jiang M, Yang P, Li M, Yang Y, et al. Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/beta-catenin signaling. Exp Cell Res. 2016;347(1):105–13.
Jiang Y, Hu X, Pang M, Huang Y, Ren B, He L, Jiang L. RRM2-mediated Wnt/beta-catenin signaling pathway activation in lung adenocarcinoma: a potential prognostic biomarker. Oncol Lett. 2023;26(4):417.
King MR, Petry S. Phase separation of TPX2 enhances and spatially coordinates microtubule nucleation. Nat Commun. 2020;11(1):270.
Hu J, He Q, Tian T, Chang N, Qian L. Transmission of Exosomal TPX2 promotes metastasis and resistance of NSCLC cells to docetaxel. Onco Targets Ther. 2023;16:197–210.
Zheng J, Li X, Cai C, Hong C, Zhang B. MicroRNA-32 and MicroRNA-548a promote the drug sensitivity of non-small cell lung cancer cells to cisplatin by targeting ROBO1 and inhibiting the activation of Wnt/beta-catenin axis. Cancer Manag Res. 2021;13:3005–16.
Zhang H, Hu B, Wang Z, Zhang F, Wei H, Li L. miR-181c contributes to cisplatin resistance in non-small cell lung cancer cells by targeting Wnt inhibition factor 1. Cancer Chemother Pharmacol. 2017;80(5):973–84.
Li J, Xu S, Dong H, Wu X, Wang LH, Xu X. Altered Wnt5a expression affects radiosensitivity of non-small cell lung cancer via the Wnt/beta-catenin pathway. Exp Ther Med. 2022;23(1):5.
Ma S, Zhang WL, Leckey BD Jr, Xu HT, Yang LH, Wang E. X-ray irradiation induced Disabled-2 gene promoter de-methylation enhances radiosensitivity of non-small-cell lung carcinoma cells. J Exp Clin Cancer Res. 2018;37(1):315.
Zhang H, Zhang K, Qiu L, Yue J, Jiang H, Deng Q, Zhou R, Yin Z, Ma S, Ke Y. Cancer-associated fibroblasts facilitate DNA damage repair by promoting the glycolysis in non-small cell lung cancer. Biochim Biophys Acta Mol Basis Dis. 2023;1869(5): 166670.
Liu J, Liu X. UBE2T silencing inhibited non-small cell lung cancer cell proliferation and invasion by suppressing the wnt/beta-catenin signaling pathway. Int J Clin Exp Pathol. 2017;10(9):9482–8.
Yin H, Wang X, Zhang X, Zeng Y, Xu Q, Wang W, Zhou F, Zhou Y. UBE2T promotes radiation resistance in non-small cell lung cancer via inducing epithelial-mesenchymal transition and the ubiquitination-mediated FOXO1 degradation. Cancer Lett. 2020;494:121–31.
Zhou Y, Xu J, Luo H, Meng X, Chen M, Zhu D. Wnt signaling pathway in cancer immunotherapy. Cancer Lett. 2022;525:84–96.
Wang B, Tian T, Kalland KH, Ke X, Qu Y. Targeting Wnt/beta-catenin signaling for cancer immunotherapy. Trends Pharmacol Sci. 2018;39(7):648–58.
Kerdidani D, Chouvardas P, Arjo AR, Giopanou I, Ntaliarda G, Guo YA, Tsikitis M, Kazamias G, Potaris K, Stathopoulos GT, et al. Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma. Nat Commun. 2019;10(1):1405.
Muto S, Ozaki Y, Yamaguchi H, Mine H, Takagi H, Watanabe M, Inoue T, Yamaura T, Fukuhara M, Okabe N, et al. Tumor beta-catenin expression is associated with immune evasion in non-small cell lung cancer with high tumor mutation burden. Oncol Lett. 2021;21(3):203.
Zhang Q, Zhao M, Lin S, Han Q, Ye H, Peng F, Li L. Prediction of prognosis and immunotherapy response in lung adenocarcinoma based on CD79A, DKK1 and VEGFC. Heliyon. 2023;9(8): e18503.
Liu Y, Qi X, Donnelly L, Elghobashi-Meinhardt N, Long T, Zhou RW, Sun Y, Wang B, Li X. Mechanisms and inhibition of Porcupine-mediated Wnt acylation. Nature. 2022;607(7920):816–22.
Tang Y, Jiang M, Chen A, Qu W, Han X, Zuo J, Xu G, Song Y, Chen C, Ke X. Porcupine inhibitor LGK-974 inhibits Wnt/β-catenin signaling and modifies tumor-associated macrophages resulting in inhibition of the malignant behaviors of non-small cell lung cancer cells. Mol Med Rep. 2021;24(2):550.
Lee HJ, Min HY, Yong YS, Ann J, Nguyen CT, La MT, Hyun SY, Le HT, Kim H, Kwon H, et al. A novel C-terminal heat shock protein 90 inhibitor that overcomes STAT3-Wnt-beta-catenin signaling-mediated drug resistance and adverse effects. Theranostics. 2022;12(1):105–25.
Li F, Cui H, Jin X, Gong X, Wang W, Wang J. Triptolide inhibits epithelial-mesenchymal transition and induces apoptosis in gefitinib-resistant lung cancer cells. Oncol Rep. 2020;43(5):1569–79.
Tian Y, Li P, Xiao Z, Zhou J, Xue X, Jiang N, Peng C, Wu L, Tian H, Popper H, et al. Triptolide inhibits epithelial-mesenchymal transition phenotype through the p70S6k/GSK3/beta-catenin signaling pathway in taxol-resistant human lung adenocarcinoma. Transl Lung Cancer Res. 2021;10(2):1007–19.
Hu Y, Wu Q, Wang Y, Zhang H, Liu X, Zhou H, Yang T. The molecular pathogenesis of triptolide-induced hepatotoxicity. Front Pharmacol. 2022;13: 979307.
Reno TA, Tong SW, Wu J, Fidler JM, Nelson R, Kim JY, Raz DJ. The triptolide derivative MRx102 inhibits Wnt pathway activation and has potent anti-tumor effects in lung cancer. BMC Cancer. 2016;16:439.
Zhang X, Huang C, Cui B, Pang Y, Liang R, Luo X. Ethacrynic acid enhances the antitumor effects of afatinib in EGFR/T790M-mutated NSCLC by inhibiting WNT/beta-catenin pathway activation. Dis Markers. 2021;2021:5530673.
Katagiri H, Yonezawa H, Shitamura S, Sugawara A, Kawano T, Maemondo M, Nishiya N. A Wnt/beta-catenin signaling inhibitor, IMU1003, suppresses the emergence of osimertinib-resistant colonies from gefitinib-resistant non-small cell lung cancer cells. Biochem Biophys Res Commun. 2023;645:24–9.
Li K, Mao S, Li X, Zhao H, Wang J, Wang C, Wu L, Zhang K, Yang H, Jin M, et al. Frizzled-7-targeting antibody (SHH002-hu1) potently suppresses non-small-cell lung cancer via Wnt/beta-catenin signaling. Cancer Sci. 2023;114(5):2109–22.
Xie W, Zhao H, Wang F, Wang Y, He Y, Wang T, Zhang K, Yang H, Zhou Z, Shi H, et al. A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/beta-catenin signaling pathway. J Exp Clin Cancer Res. 2021;40(1):30.
Giraudet AL, Cassier PA, Iwao-Fukukawa C, Garin G, Badel JN, Kryza D, Chabaud S, Gilles-Afchain L, Clapisson G, Desuzinges C, et al. A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients. BMC Cancer. 2018;18(1):646.
Sudo H, Tsuji AB, Sugyo A, Harada Y, Nagayama S, Katagiri T, Nakamura Y, Higashi T. FZD10-targeted alpha-radioimmunotherapy with (225) Ac-labeled OTSA101 achieves complete remission in a synovial sarcoma model. Cancer Sci. 2022;113(2):721–32.
Diamond JR, Becerra C, Richards D, Mita A, Osborne C, O’Shaughnessy J, Zhang C, Henner R, Kapoun AM, Xu L, et al. Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer. Breast Cancer Res Treat. 2020;184(1):53–62.
Le PN, McDermott JD, Jimeno A. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther. 2015;146:1–11.