Forkhead box transcription factor 1 expression in gastric cancer: FOXM1 is a poor prognostic factor and mediates resistance to docetaxel
- Xiaoxiao Li†1,
- Wensheng Qiu†1,
- Bin Liu2,
- Ruyong Yao3,
- Shihai Liu3,
- Yasai Yao1 and
- Jun Liang1Email author
© Li et al.; licensee BioMed Central Ltd. 2013
Received: 19 June 2013
Accepted: 2 September 2013
Published: 3 September 2013
Forkhead box transcription factor 1 (FOXM1) has been reported to overexpress and correlate with pathogenesis in a variety of human malignancies. However, little research has been done to investigate its clinical significance in gastric cancer.
We examined the expression of FOXM1 in 103 postoperational gastric cancer tissues and 5 gastric cell lines by immunohistochemistry and western blot analysis respectively. Data on clinic-pathological features and relevant prognostic factors in these patients were then analyzed. Moreover, the association of FOXM1 expression and chemosensitivity to docetaxel in gastric cancer cells was further explored.
Our study demonstrated that the level of FOXM1 expression was significantly higher in gastric cancer than in para-cancer tissues (P < 0.001) and normal gastric cell lines (P = 0.026). No significant association was found between FOXM1 expression and any clinical pathological features (P > 0.1). FOXM1 amplification was identified as an independent prognostic factor in gastric cancer (P = 0.001), and its affection is more significant in patients with tumor size larger than 5 cm (P = 0.004), pT3-4 (P = 0.003) or pIII-IV (P = 0.001). Additionally, shown to mediate docetaxel resistance in gastric cancers by our research, FOXM1 was revealed to alter microtubule dynamics in response to the treatment of docetaxel, and the drug resistance could be reversed with FOXM1 inhibitor thiostrepton treatment.
FOXM1 can be a useful marker for predicting patients’ prognosis and monitoring docetaxel response, and might be a new therapeutic target in docetaxel resistant gastric cancer.
KeywordsFOXM1 Gastric cancer Prognosis Docetaxel resistance
Despite the developments of surgical technique and improvements of anticancer drugs recently, gastric cancer is still the main cause of death and strongly associated with poor outcome. So far, in China, the morbidity of gastric cancer has reached to second with 3,621,000 new cases, whilst the mortality rate ranked third with the proportion of 14.33% each year . Most patients present with metastatic or unresectable disease at the time of diagnosis . For these surgically unfit but medically fit patients, palliative chemotherapy is the main choice of treatment. Among new generation chemotherapy regimens, docetaxel, which is a semisynthetic taxane, promoting the assembly and stabilization of microtubules to inhibit the depolymerization , has been used more and more extensively with potent effects [4–6]. The chemotherapy regimen of docetaxel, cisplatin and 5-fluorouracil (DCF) has been commonly used to treat the advanced stage or metastatic gastric carcinoma with encouraging survival outcomes [7–12] and better quality of life [13, 14]. Yet, resistance to docetaxel does occur in gastric cancers . Thus, identification of some suitable biomarkers for predicting patient prognosis and chemosensitivity is significant for improving therapeutic effects for patients with advanced gastric cancer.
Forkhead box protein M1 (FOXM1), characterised by a 100 amino acid winged-helix DNA binding domain, is a newly unified family member of Forkhead transcription factor . Previous researches indicated that FOXM1, activated by the Ras-MAPK and hedgehog signaling pathway [17, 18], played an important role in cell cycle by promoting both the transition from G1 to S phase and progression to mitosis through genes of Cdc25B, CDK1 and p27KIP et al. [19, 20]. It was demonstrated that FOXM1 overexpressed in gastric cancer and that elevated FOXM1 promoted tumor development in various kinds of cancers, correlated closely with poor outcome [21–23]. Additionally, in current research, FOXM1 amplification was reported to confer primary resistance of gefitinib in non-small cell lung cancer (NSCLC) and acquired paclitaxel resistance in breast cancer, showing implications in resistance to chemotherapy strongly [24, 25]. These results suggested that FOXM1 may play an important role in progression of human cancers and may be associated with the resistance to docetaxel. Although FOXM1 has been revealed to mediate promotion of human gastric cancer angiogenesis, growth, and metastasis , the clinical significance of FOXM1 overexpression in gastric cancer is still little explored yet.
In current study, we examined the expression of FOXM1 protein in both gastric cancer specimens and cell lines, and assessed correlations among FOXM1 overexpression, clinic-pathological characteristics and clinic outcome. In addition, we investigated the relationship between overexpression of FOXM1 and docetaxel resistance in gastric cancer cells, trying to provide a support to its clinical significance in clinical practice.
Materials and methods
Human tissue specimens and patient information
Gastric cancer tissues were obtained from 103 patients who underwent gastrectomy and D2 lymphadenectomy at the Affiliated Hospital of Qingdao University Medical College from Jan 2007 to Nov 2007. 68 para-cancer tissues which were more than 5 cm away from the edge of tumor were randomly selected. All patients meet the criteria: 1) Tumors were confirmed to be gastric adenocarcinoma histologically. 2) None had received any preoperative treatment such as chemotherapy or radiotherapy. 3) Everyone was available of follow-up data. Clinic-pathological information was obtained from patient’s operative and pathological reports, in which age (≤50 years or >50 years), gender, size of tumor (≤5 cm or >5 cm), depth of tumor invasion (T1: tumor has invaded the mucosa or submucosa layer; T2: tumor has invaded the muscular layer; T3: tumor has invaded subserosa; T4: tumor invaded serosa or adjacent organs), lymph node metastasis, degree of differentiation (undifferentiated or differentiated),venous invasion, neural invasion, Borrmann type (Borrmann I, II, III, IV), Lauren type (intestinal, diffuse, mixed) and the 7th American Joint Committee on Cancer (AJCC) TNM stage (I, II, III, IV) were included.
Cell lines and culture conditions
Three gastric cancer cell lines, SGC-7901, AGS, and MKN-28 and two normal gastric epithelium cell lines, GES-1 and HFE-145 were obtained from the central laboratory of Affiliated Hospital of Qingdao University Medical College. All these five cell lines were cultured in RPMI 1640 (Thermo scientific, CA), supplemented with 10% FBS (Thermo scientific, CA) and 1% Penicillin/Streptomycin (Invitrogen, Tokyo, Japan), and incubated in 5% CO2 at 37°C. The semisynthetic taxane, docetaxel (Selleckchem, US), was dissolved in dimethyl sulfoxide (DMSO) and diluted to a final concentration of 0.015 mg/L and 0.020 mg/L before use.
The expression of FOXM1 was detected through immunohistochemistry (IHC) analyses with 3-um-thick sections of formalin-fixed and paraffin-embedded blocks. For IHC staining, tissue sections were dewaxed in xylene and rehydrated gradually with graded ethanol. For antigen retrieval, all the sections were incubated by microwave oven in citrate buffer solution (pH 6.0) for 20 minutes. Endogenous peroxidase was inactived by 0.3% hydrogen peroxide in methanol for 15 min. After that, tissue slides were incubated with rabbit polyclonal antibody against human FOXM1 (dilution 1:100, Epitomics, US) at 4°C overnight and then visualized antibody binding sites with the SP peroxidase detection system. Finally, sections were incubated in 3,3’-diaminobenzidine tetrahydrochloride for 3–10 minutes and restained with 0.1% hematoxylin. In every case, negative control reaction was set with PBS replacing FOXM1 antibody, while the known positive-stained section was used as positive control. The results of IHC were evaluated by two pathologists independently with no knowledge of clinic-pathological features.
The expression of FOXM1 was scored by multiplying the intensity scores and the percentage area positively stained [27, 28]. Briefly, the intensity score was categorized into four groups: no staining marked 0; weak staining marked 1; moderate staining marked 2 and strong staining marked 3. For the percentage of positively stained cells, the scores were sorted from 0 to 4 (<5% marked 0; 5%-25% marked 1; 25%-50% marked 2; 51%-75% marked 3; 75% marked 4). After such calculation, the finally composite scores were divided into four grades: 0–1 were negative, 2–4 were weakly positive, 5–8 were moderately positive and 9–12 were strongly positive. 2 and more than 2 scores were evaluated as positive results.
Western blot analysis
Whole-cell lysates were prepared from gastric cancer cell lines which were in logarithmic growth phase or at indicated periods of time. Total proteins were fractionated using sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred onto Polyvinylidene fluoride membrane. Anti-FOXM1 (dilution 1:1000, Epitomics, US) and anti-GAPDH (dilution 1:2000, CWBIO, CA) rabbit polyclonal antibodies were used as primary antibodies. For tubulin fractionation, α-tubulin antibody (1:1000, Santa, US) and β-tubulin antibody (1:1000, Santa, US) were used for analysis. The signals were detected using the VILBER enhanced chemiluminescence system (VILBER LOURMAT, FRA) according to the manufacturer’s instructions. Results shown were derived from at least three independent experiments.
For MTT assays, 5000 cells were seeded overnight in 96-well plates and then cultured in 100 μL of fresh medium that contained various concentrations of docetaxel for 24–72 hours. Each concentration was repeated in triplicate. After that, MTT solution (20 μL, 5 mg/mL in PBS) was added to each well and the plate was incubated at 37°C for 4 hours. The solution was then removed and 200 μL of DMSO was added to each well. After 10 minutes of vibration mixing, the optical density (OD) at 490 nm was measured using a microplate reader (Bio RAD, US).
Plasmids and transfections
The human FOXM1 expression vector pcDNA3.1-FOXM1 and siRNA-FOXM1 were obtained from the center library of Affiliated Hospital of Qingdao University Medical College. For transfections, cells were seeded to a 40–50% confluence state and transfected with pcDNA3.1-FOXM1, siRNA-FOXM1 or pcDNA3.1 with Lipofectamine 2000 agent (Invitrogen, US) in accordance with the manufacturer’s protocol. After transfection, cells were cultured for 48 h and analyzed by western blotting and MTT assay.
Total cellular RNA was extracted from cell pellets of each cell lines with Trizol reagent. The amount of RNA was determined by BJKO assay system (BJKO, CA), and part of them was reverse transcribed using the Reverse Transcription System (TaKaRa, CA). The primer sequences for PCR amplification were as follows: FOXM1 sense 5′- TAT TCA CAG CAT CAT CAC AGC A-3′ and antisense 5′- GAA GGC TCC TCA ACC TTA ACC T-3′; GAPDH sense 5′- ACC ACA GTC CTG CAT GCC AC -3′ and antisense 5′ - TCC ACC ACC CTG TTG CTG TA -3′. To ensure experiment accuracy, all reactions were performed in triplicate. The integrity of all RNA samples was verified by RT-PCR for GAPDH in each sample through gel imaging systerm (VILBER LOURMAT, FRA). The value of FOXM1 expression was divided by that of GAPDH in each sample.
Molecular evolution assay
The gastric cancer cell line AGS was treated with 0.015 mg/L docetaxel for 72 hours when cells reached a confluency of 80%. After treatment, docetaxel containing medium was replaced by fresh medium. As soon as cells recovered, they were seeded for RNA isolation, cell lysis (protein), MTT assays and the next treatment cycle. In this manner, several rounds of molecular evolution assay were performed. To obtain the appropriate rate of cell death in the molecular evolution assay, several docetaxel concentrations were tested in a preliminary experiment. Thereby, 0.015 mg/L was obtained as the most suitable concentration.
Separation of polymerized and soluble fractions was done in accordance with previously published assays . Cells were seeded at 80% confluency in 24-well plates. The following day they were treated with 0 or 0.020 mg/L docetaxel for 48 hours. Cells were collected in hypotonic buffer (1 mM MgCl2, 2 mM EGTA, 0.5% Nonidet P-40, 20 mM Tris–HCl pH 6.8) and centrifuged for 10 minutes at room temperature (14,000 rpm). The supernatant was used as the soluble fraction while the pellet made up the polymerized fraction. Samples were analyzed by western blot.
We performed a 5-year retrospective, cohort research for individual patients after gastric cancer surgery from 2007 to 2012. The median duration of follow-up was 49.2 months (range, 7–60 months). For patients who remained alive until the cut-off date, survival data were recorded as 60 months. The information about survival was collected in the Oncology Department of the Affiliated Hospital of Medical College Qingdao University. Also, informed consent was obtained from all the patients. The ethical committee of our institute approved the research protocol for this study.
We used Chi-Square statistical test to identify correlations in the human gastric cancer clinic-pathological parameters and Log-rank analysis for the in vivo (patients) survival study. In addition, we evaluated significant differences in vitro data using Student’s t-test. A significance level set at p < 0.05 was considered significant for all the tests.
FOXM1 protein expression in gastric cancer tissues and cell lines
Different FOXM1 expressions in gastric cancer tissues and paraneoplastic tissues
Association between FOXM1 expression and clinic-pathological factors in 103 patients after gastrectomy
Entire group (n = 103)
Depth of tumor invasion
Lymph node metastasis
Degree of differentiation
Bomann histologic classifications (n = 77)
To further confirm that results in vitro, we next investigated the level of FOXM1 expression in benign and malignant human gastric cell lines by western blot analysis. As a result, the gastric cancer cell lines equally exhibited 6-fold more FOXM1 expression compared with the normal ones (Figure 1B, P = 0.026), in which a homogenous FOXM1 expression was showed in the gastric epithelium cell lines such as GES-1 and HFE-145, whereas FOXM1 expression levels were more heterogeneous and in total elevated in cancerous cell lines, demonstrating that FOXM1 also overexpressed in human gastric cancer cell lines.
Prognostic significance of FOXM1 expression in survival of gastric cancer patients
Results of univariate and multivariate analysis of 5-year survival by Cox proportional hazard model
Age (≤50 years / >50 years)
Size of tumor (≤5 cm / >5 cm)
Depth of tumor invasion (T1-2/T3-4)
Lymph node metastatis (negative/positive)
Degree of differentiation (undifferentiated/differentiated)
Venous invasion (negative/positive)
Neural invasion (negative/positive)
FOXM1 expession (negative/positive)
TNM staging (I-II/III-IV)
Lauren type (intestinal/diffuse and mixed)
Results of tumor size, pT, and pTNM stage-stratified analysis according to FOXM1 expression
FOXM1 expression levels of cell lines and sensitivity to docetaxel
Molecular evolution of gastric cancer cells lead to a docetaxel resistant phenotype and up-regulation of FOXM1
FOXM1 confers resistance to docetaxel by altering microtubule dynamics in preventing docetaxel induced apoptosis
Several mechanisms to combat palitaxol induced apoptosis have been reported previously. Namely, up-regulation of MDR1 (multi-drug resistant protein 1), a P-Glycoprotein family member can shuttle toxins out of cells; up-regulation of the CIAP (inhibitors of apoptosis) family members including Survivin; and the altered microtubule dynamics . Given the overlapping roles of docetaxel and FOXM1 upon affecting the microtubule dynamics of mitosis progression in tumor cells, we suggested hypothesis that altered microtubule dynamics mediated by FOXM1 could prevent docetaxol induced apoptosis, which caused docetaxel resistance in gastric cancers.
Thiostrepton can overcome docetaxel resistance in gastric cancer cells through down-regulation of FOXM1
In current study, we demonstrated that the level of FOXM1 expression was significantly higher in gastric cancer than in para-cancer tissues and normal gastric cell lines. Although no significant association was found between FOXM1 expression and any clinical pathological features, FOXM1 amplification was identified as an independent prognostic factor in gastric cancer, and its affection is more significant in patients with advanced stage. Moreover, shown to mediate docetaxel resistance in gastric cancers, FOXM1 was revealed to interfere in microtubule polymerization after the treatment of docetaxel in our research. When we attenuated FOXM1 expression with FOXM1 inhibitor thiostrepton, docetaxel resistance in gastric cancers could be reversed, simultaneously with the down-regulation of FOXM1.
Forkhead transcription factor is a new family of transcription factors, which was officially unified in 2000 . In previous studies, FOXM1 was revealed to promote cell cycle by directly activating its downstream genes [19, 20]. Furthermore, the overexpressed FOXM1 could simultaneously induce gastric cancer angiogenesis and progression through regulating the level of VEGF (vascular endothelial growth factor) gene expression and correlating with MVD (microvessel density) . These researches may explain why no association was found between FOXM1 expression and clinical pathological parameters, for the clinical features such as tumor size, depth of invasion and lymph node metastasis cannot fully represent the proliferation activity of the tumor cells, whereas FOXM1 mainly reflected the division of cells. This result was agreed with Kaoru Okada’s study, which also detected the expression of FOXM1 in gastric cancer and showed the positive expression did not correlate with any clinic-pathological features . Moreover, overexpression of FOXM1 was previously reported to contribute to the elevated migratory and invasive abilities in oral cavity squamous cell carcinoma , indicating that FOXM1 was associated with an aggressive behavior of tumor cells in vitro. These hypotheses were further provided by our results, which showed that FOXM1 is an independent prognostic factor in gastric cancer. Additionally, in order to address the confound influence of other independent prognostic factors, we performed the size, pT and pTNM stratified analysis according to FOXM1 expression levels. As a result, the prognosis was significantly poorer for patients with positive FOXM1 expression when limited to the same tumor size (>5 cm), depth of invasion (T3 and T4) or TNM stage (III-IV), whilst no significant relationship was found between FOXM1 expression and survival duration for patients with stage T1-2, I-II and smaller tumor size. It can be speculated that some other factor may be more significant than FOXM1 in predicting the prognosis at early stage, such as lymph node metastasis , whereas in advanced stage, angiogenesis, which is promoted by FOXM1, may influence the growth velocity of tumor more significantly . Based on these results, it is considerately that FOXM1 should be combined with the tumor size, T stage and TNM stage for predicting the prognosis of gastric cancer, and further studies should focus on exploring the mechanism of FOXM1 on promoting the adverse progression of advanced gastric cancers.
In gastric cancer treatment, classical chemotherapy is largely used besides surgery operation, radiotherapy and novel targeted therapy approaches. For instance, docetaxel is commonly used as single-agent or in combination with other drugs like platinum and fluoropyrimidine (DCF regimen) in a neo-adjuvant or advanced stage setting [34, 35]. The chemotherapy based on docetaxel may be effective, because docetaxel was reported to lack cross-resistance with other anti-tumor drugs . However, the resistance to docetaxel did occur and FOXM1 was shown to be a critical molecular for that resistance in gastric cancer by our current research, for which elevated levels of FOXM1 was shown to correlate with lower drug susceptibility, whilst the molecular evolution assay of AGS resulted in significantly more resistant cells possessed FOXM1 overexpression. Additionally, Carr et al. have reported that FOXM1 functioned chemoresistance to a microtubule stabilizing anticancer drug, paclitaxel by directly regulating the microtubule destabilizing protein Stathmin and altering dynamics of microtubule in breast cancer . As docetaxel is also an anticancer agent, which binds to β-tubulin and stabilizes microtubules consisting α/β-tubulin dimers, resulting in mitotic failure like paclitaxel, the same mechanism should occur in gastric cancer cells. Accordingly, through tubulin assay analysis, we found that microtubules in FOXM1 overexpressed cell lines fail to polymerize in response to docetaxol treatment, indicating that FOXM1 did prevent docetaxol induced apoptosis by altering the microtubule dynamics in gastric cancer, however, the downstream genes of FOXM1 was not revealed by our research yet. Moreover, after treated cells with FOXM1 inhibitor thiostrepton, the acquired drug resistance was reversed with the down-regulation of FOXM1 expression, demonstrating the inactivation of FOXM1 was essential for reversing docetaxel resistance and targeting FOXM1 could potentially be a better therapeutic strategy for overcoming the resistance to docetaxel. Nevertheless, this inhibitory effect on FOXM1 has not been analyzed for human gastric cancer so far. Therefore, further studies should be focused on the anti-tumor function of FOXM1 inhibitors, especially in docetaxel-resistant gastric cancer.
In conclusion, our study showed that FOXM1 was an independent prognostic factor for gastric cancer patients. Further, we also showed that FOXM1 is a critical mediator of docetaxel sensitivity and resistance in gastric cancer cells. Therefore, FOXM1 can be a useful marker for predicting patients’ prognosis and monitoring docetaxel response, which might be a new therapeutic target in docetaxel resistant gastric cancer.
Forkhead box transcription factor 1
Chemotherapy regimen of docetaxel cisplatin and 5-fluorouracil
Non-small cell lung cancer
The 7th American Joint Committee on Cancer
Multi-drug resistant protein 1
Vascular endothelial growth factor
Micro vessel density.
This study is supported by the grant of Medicine and healthy technology development program of Shandong province (2011HZ028).
- Chen W, Zheng R, Zhang S, Zhao P, Li G, Wu L, He J: The incidences and mortalities of major cancers in China, 2009. Chin J Cancer. 2013, 32: 106-112. 10.5732/cjc.013.10018.PubMed CentralView ArticlePubMedGoogle Scholar
- Ohtsu A: Chemotherapy for metastatic gastric cancer: past, present, and future. J Gastroenterol. 2008, 43: 256-264. 10.1007/s00535-008-2177-6.View ArticlePubMedGoogle Scholar
- Fumoleau P, Perrocheau G, Maugard-Louboutin C, Lemevel B: Paclitaxel (Taxol) and docetaxel (Taxotere): results of phase II trials in monochemotherapy. Bull Cancer. 1995, 82: 629-636.PubMedGoogle Scholar
- Haller DG, Misset JL: Docetaxel in advanced gastric cancer. Anticancer Drugs. 2002, 13: 451-460. 10.1097/00001813-200206000-00003.View ArticlePubMedGoogle Scholar
- Giuliani F, Gebbia V, De Vita F, Maiello E, Di Bisceglie M, Catalano G, Gebbia N, Colucci G: Docetaxel as salvage therapy in advanced gastric cancer: a phase II study of the Gruppo Oncologico Italia Meridionale (G.O.I.M.). Anticancer Res. 2003, 23: 4219-4222.PubMedGoogle Scholar
- Chen XZ, Jiang K, Hu JK, Zhang B, Gou HF, Yang K, Chen ZX, Chen JP: Cost-effectiveness analysis of chemotherapy for advanced gastric cancer in China. World J Gastroenterol. 2008, 14: 2715-2722. 10.3748/wjg.14.2715.PubMed CentralView ArticlePubMedGoogle Scholar
- Ajani JA: Docetaxel for gastric and esophageal carcinomas. Oncol (Williston Park). 2002, 16: 89-96.Google Scholar
- Oh DY, Kim TY, Kwon JH, Lee JJ, Joh Y, Kim DW, Heo DS, Bang YJ, Kim NK: Docetaxel + 5-fluorouracil + cisplatin 3-day combination chemotherapy as a first-line treatment in patients with unresectable gastric cancer. Jpn J Clin Oncol. 2005, 35: 380-385. 10.1093/jjco/hyi107.View ArticlePubMedGoogle Scholar
- Oh SC, Park KH, Choi IK, Yoon SY, Kim SJ, Seo JH, Choi CW, Kim BS, Shin SW, Kim JS, Kim YH: Docetaxel (Taxotere), cisplatin, UFT, and leucovorin combination chemotherapy in advanced gastric cancer. Br J Cancer. 2005, 92: 827-831. 10.1038/sj.bjc.6602446.PubMed CentralView ArticlePubMedGoogle Scholar
- Park SR, Chun JH, Kim YW, Lee JH, Choi IJ, Kim CG, Lee JS, Bae JM, Kim HK: Phase II study of low-dose docetaxel/fluorouracil/cisplatin in metastatic gastric carcinoma. Am J Clin Oncol. 2005, 28: 433-438. 10.1097/01.coc.0000162424.69631.79.View ArticlePubMedGoogle Scholar
- Lorenzen S, Hentrich M, Haberl C, Heinemann V, Schuster T, Seroneit T, Roethling N, Peschel C, Lordick F: Split-dose docetaxel, cisplatin and leucovorin/fluorouracil as first-line therapy in advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: results of a phase II trial. Ann Oncol. 2007, 18: 1673-1679. 10.1093/annonc/mdm269.View ArticlePubMedGoogle Scholar
- Ajani JA, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E: Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group. J Clin Oncol. 2007, 25: 3205-3209. 10.1200/JCO.2006.10.4968.View ArticlePubMedGoogle Scholar
- Ajani JA, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E: Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group. J Clin Oncol. 2007, 25: 3210-3216. 10.1200/JCO.2006.08.3956.View ArticlePubMedGoogle Scholar
- Sadighi S, Mohagheghi MA, Montazeri A, Sadighi Z: Quality of life in patients with advanced gastric cancer: a randomized trial comparing docetaxel, cisplatin, 5-FU (TCF) with epirubicin, cisplatin, 5-FU (ECF). BMC Cancer. 2006, 6: 274-10.1186/1471-2407-6-274.PubMed CentralView ArticlePubMedGoogle Scholar
- Suzuki T, Yoshida K, Wada Y, Hamai Y, Sentani K, Oue N, Yasui W: Melanoma-associated antigen-A1 expression predicts resistance to docetaxel and paclitaxel in advanced and recurrent gastric cancer. Oncol Rep. 2007, 18: 329-336.PubMedGoogle Scholar
- Wierstra I, Alves J: FOXM1, a typical proliferation-associated transcription factor. Biol Chem. 2007, 388: 1257-1274.PubMedGoogle Scholar
- Ma RY, Tong TH, Leung WY, Yao KM: Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1. Methods Mol Biol. 2010, 647: 113-123. 10.1007/978-1-60761-738-9_6.View ArticlePubMedGoogle Scholar
- Katoh Y, Katoh M: Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med. 2009, 9: 873-886. 10.2174/156652409789105570.View ArticlePubMedGoogle Scholar
- Wang IC, Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ, Tan Y, Ackerson T, Costa RH: Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol Cell Biol. 2005, 25: 10875-10894. 10.1128/MCB.25.24.10875-10894.2005.PubMed CentralView ArticlePubMedGoogle Scholar
- Costa RH: FoxM1 dances with mitosis. Nat Cell Biol. 2005, 7: 108-110. 10.1038/ncb0205-108.View ArticlePubMedGoogle Scholar
- Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Aldape KD, Xie TX, Pelloski CE, Xie K: FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Cancer Res. 2006, 66: 3593-3602. 10.1158/0008-5472.CAN-05-2912.View ArticlePubMedGoogle Scholar
- Yau C, Wang Y, Zhang Y, Foekens JA, Benz CC: Young age, increased tumor proliferation and FOXM1 expression predict early metastatic relapse only for endocrine-dependent breast cancers. Breast Cancer Res Treat. 2011, 126: 803-810. 10.1007/s10549-011-1345-1.PubMed CentralView ArticlePubMedGoogle Scholar
- Okada K, Fujiwara Y, Takahashi T, Nakamura Y, Takiguchi S, Nakajima K, Miyata H, Yamasaki M, Kurokawa Y, Mori M, Doki Y: Overexpression of forkhead box M1 transcription factor (FOXM1) is a potential prognostic marker and enhances chemoresistance for docetaxel in gastric cancer. Ann Surg Oncol. 2013, 20: 1035-1043. 10.1245/s10434-012-2680-0.View ArticlePubMedGoogle Scholar
- Xu N, Zhang X, Wang X, Ge HY, Wang XY, Garfield D, Yang P, Song YL, Bai CX: FoxM1 mediated resistance to gefitinib in non-small-cell lung cancer cells. Acta Pharmacol Sin. 2012, 33: 675-681. 10.1038/aps.2011.188.PubMed CentralView ArticlePubMedGoogle Scholar
- Carr JR, Park HJ, Wang Z, Kiefer MM, Raychaudhuri P: FoxM1 mediates resistance to herceptin and paclitaxel. Cancer Res. 2010, 70: 5054-5063. 10.1158/0008-5472.CAN-10-0545.PubMed CentralView ArticlePubMedGoogle Scholar
- Li Q, Zhang N, Jia Z, Le X, Dai B, Wei D, Huang S, Tan D, Xie K: Critical role and regulation of transcription factor FoxM1 in human gastric cancer angiogenesis and progression. Cancer Res. 2009, 69: 3501-3509. 10.1158/0008-5472.CAN-08-3045.PubMed CentralView ArticlePubMedGoogle Scholar
- Remmele W, Stegner HE: Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987, 8: 138-140.PubMedGoogle Scholar
- Halon A, Donizy P, Biecek P, Rudno-Rudzinska J, Kielan W, Matkowski R: HER-2 expression in immunohistochemistry has no prognostic significance in gastric cancer patients. ScientificWorldJournal. 2012, 2012: 941259-PubMed CentralView ArticlePubMedGoogle Scholar
- Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB: Mechanisms of Taxol resistance related to microtubules. Oncogene. 2003, 22: 7280-7295. 10.1038/sj.onc.1206934.PubMed CentralView ArticlePubMedGoogle Scholar
- Kwok JM, Myatt SS, Marson CM, Coombes RC, Constantinidou D, Lam EW: Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression. Mol Cancer Ther. 2008, 7: 2022-2032. 10.1158/1535-7163.MCT-08-0188.View ArticlePubMedGoogle Scholar
- Kaestner KH, Knochel W, Martinez DE: Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 2000, 14: 142-146.PubMedGoogle Scholar
- Chen CH, Chien CY, Huang CC, Hwang CF, Chuang HC, Fang FM, Huang HY, Chen CM, Liu HL, Huang CY: Expression of FLJ10540 is correlated with aggressiveness of oral cavity squamous cell carcinoma by stimulating cell migration and invasion through increased FOXM1 and MMP-2 activity. Oncogene. 2009, 28: 2723-2737. 10.1038/onc.2009.128.View ArticlePubMedGoogle Scholar
- Zu H, Wang F, Ma Y, Xue Y: Stage-stratified analysis of prognostic significance of tumor size in patients with gastric cancer. PLoS One. 2013, 8: e54502-10.1371/journal.pone.0054502.PubMed CentralView ArticlePubMedGoogle Scholar
- Tebbutt NC, Cummins MM, Sourjina T, Strickland A, Van Hazel G, Ganju V, Gibbs D, Stockler M, Gebski V, Zalcberg J: Randomised, non-comparative phase II study of weekly docetaxel with cisplatin and 5-fluorouracil or with capecitabine in oesophagogastric cancer: the AGITG ATTAX trial. Br J Cancer. 2010, 102: 475-481. 10.1038/sj.bjc.6605522.PubMed CentralView ArticlePubMedGoogle Scholar
- Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E: Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006, 24: 4991-4997. 10.1200/JCO.2006.06.8429.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.