Skip to main content

Role of estrogen in hepatocellular carcinoma: is inflammation the key?


Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and accounts for the third-leading cause of cancer-related deaths. Over the past decades, advances have been made in the field of surgery, but effective treatment of HCC is lacking. Due to a marked male predominance in morbidity and mortality in HCC patients, it has long been considered that sex hormones play a role in HCC development. Recently estrogen has been proven to exert protective effects against HCC through IL-6 restrictions, STAT3 inactivation and tumour-associated macrophage inhibition. While IL-6-dependent STAT3 activation is considered a key event in inflammation-induced liver cancer, the anti-inflammation effect of estrogen is well documented. The roles of the estrogen receptor and aromatase and interactions between microRNAs and estrogen in HCC have been investigated. In this review, we present a novel model to elucidate the mechanism of estrogen-mediated inhibition of HCC development through an anti-inflammation effect and provide new insights into the roles of estrogen in liver disease.


The treatment of liver cancer is a difficult task, especially among end-stage patients, whose lesions are usually thought to be unresectable. The development of HCC is considered the end result of most liver diseases, including viral hepatitis, cirrhosis and alcoholic liver disease. As a result of high-grade malignancy and lack of effectiveness of medical treatment, HCC is the third-leading cause of cancer deaths worldwide [1]. Furthermore, the incidence of HCC shows a regional divergence due to aetiology. In high-risk areas such as Southeast Asia and China, hepatitis B virus (HBV) infection, together with aflatoxin exposure, is the predominant risk factor. However, hepatitis C virus (HCV) infection has emerged as a more significant risk factor in Japan, North America and Europe. In these developed countries, the incidence of HCC is increasing [2, 3].

Until now, only sorafenib is used as first-line therapy for patients with advanced HCC [4, 5]. Sorafenib therapy for HCC has been proven to be safe and effective. Despite a statistically significant and clinically relevant improvement in median overall survival (OS) with sorafenib, some important questions of its application in advanced HCC remain unanswered [6]. For the better use of sorafenib in the clinical setting, the dosage, outcome prediction based on side effects and application of modified Response Evaluation Criteria in Solid Tumours (mRECIST) require more evaluation. Interested in obvious gender disparity in HCC occurrence [7, 8], researchers have attempted to investigate the molecular mechanism underlying such disparity and developed effective therapy using sex hormones. Recently, work by Ma et al. showed an exciting potential of the combination of sorafenib and hormone-related therapy in HCC, which will be a better way to control advanced HCC [9].

Unlike breast and prostate cancer, which are modulated by estrogen and androgen, respectively, HCC may be modulated by both sex hormones during its initiation, progression and metastasis [8, 10, 11]. Elevated levels of androgen are considered to promote tumourigenesis, while studies in the past decades showed that the roles of estrogen in HCC are diverse, even opposite [8, 1214]. Fortunately, recent progress has shed some light on the precise mechanism of estrogen action in HCC. Although many aspects are still unknown, the anti-HCC activity of estrogen has been wildly accepted, and its protective effect might be related to its anti-inflammation effect. We thus assume that this anti-inflammation effect may provide a key to understanding the role of estrogen in HCC. More importantly, the anti-inflammation nature of estrogen may yield a new, promising approach to treat HCC. In this review, we focus on recent studies regarding the potential roles of estrogen in HCC.

Early clinical trials of anti-estrogen therapy for HCC

At the very beginning of anti-estrogen therapy in medical practice, clinicians were inspired by the success of tamoxifen, which is a competitive antagonist of the estrogen receptor (ER), as a treatment for ER-positive breast cancer. In addition, estrogen was found to promote HCC in rats [1519]. Some reports also showed that oral contraceptives (OCPs) led to a higher incidence of liver diseases such as focal nodular hyperplasia, liver haemangioma and hepatocellular adenoma, which are considered premalignant stages of HCC [20, 21]. However, a systematic review concluded that no benefits could be gained by anti-estrogen in regards to overall survival and life quality [22]. And it is also suggested that OCPs might not to be a risk factor for HCC [23]. As a result, several hypotheses were proposed to explain the failures of using anti-estrogen in treating HCC, including the dysfunction induced by variant ER-α (vER-α) [24, 25], regulation by the postreceptor signalling pathway and treatment with an insufficient therapy dose [26, 27]. With further investigations, estrogen was found to suppress HCC [28], and this was supported by epidemiology data, which suggested an elevated incidence of HCC in postmenopausal female and suppression of such phenomenon by estrogen treatment [29, 30]. Moreover, the prognosis of female HCC patients is much better than male patients [31]. These findings all imply that estrogen may act as a protective factor against HCC. Unfortunately, estrogen-related treatment is still impractical so far due to our limited knowledge [22].

ER-α may be crucial to the estrogen-induced effect on HCC

The initiation of the canonical estrogen pathway depends on the binding of estrogen and its receptor. The ligand-bound ER then recognizes the estrogen response element (ERE) and regulates the transcription of target genes. Two subtypes of ERs have been found to date, ER-α and ER-β. Both ER subtypes are expressed in HCC and interact with each other [32]. Studies have shown that ER subtypes exert multiple functions in various stages of liver disease and participate in an extremely complicated signal transduction process. The different roles of the ER subtypes in liver disease, especially ER-β, have yet to be fully elucidated. Nevertheless, ER-α has been identified for a long time and has been extensively investigated [8].

Wild type ER-α (wtER-α) contains 595 amino acid residues with a molecular mass of 66 kDa. It consists of a ligand-independent activation function domain (AF-1), a central DNA-binding domain (DBD) and a hormone-binding domain (HBD, also named ligand-dependent activation function domain, AF-2). The DBD and the HBD are linked by a hinge region [33]. Different ER-α splice variants, including ER-αΔ5 (incomplete HBD), ERα-46 (AF-1 deleted) and ERα-36 (AF-1 deleted and incomplete HBD), have been identified in the liver (Figure 1) [34, 35]. The ER-α variants have been proven to be strong negative predictors for HCC [25, 36, 37]. ER-αΔ5 and hepatitis B virus X protein (HBx) can repress the transcriptional activity of wtER-α through an 17β-estradiol (E2)-independent method, and histone deacetylase-1 (HDAC-1) seems to be involved in the process [38].

Figure 1

Four types of ER-α variants in the liver. Alternative splicing events generate several different isoforms of ER-α. In the liver, all types of ER-α have been reported and play a role in HCC. These variants are mainly AF-1- or HBD-depleted. ERα-36 has an additional 27-amino-acid sequence at its COOH terminus.

A different expression pattern of vER-α can be observed in normal liver, cirrhosis and HCC tumour tissues (Table 1) [34], and a similar result can be obtained in liver cell lines. Furthermore, ER-α seems to lose function during liver disease progression, and dysfunctional ER-α could contribute to HCC development. In addition, ERα-36 negatively regulates the transcriptional activity of ER-66 and ER-β [39]. This crosstalk between ER subtypes forms a part of the complex ER signalling and has yet to be confirmed in HCC.

Table 1 The expression pattern of ER-α subtypes in different liver tissues

However, vER-α is considered a predictor of poor prognosis both in HCC and breast cancer [33]. In multiple-factor analysis, the ER-α type and bilirubin level were two independent risk factors for HCC [36]. The worst prognosis appears in patients with vER-α and hepatitis B surface antigen (HBS-Ag), and this may be explained by the suppression of transcriptional activity of the ER-α by HBx and ER-αΔ5. In addition, HBV infection could lead to genomic instability, which may contribute to the expression of vER-α [40]. Although tumour size was not obviously different in groups with different ERα types, vER-α-positive HCC presents a rapid growth rate and an increased ability of metastasis [36]. Therefore, vER-α-positive patients usually die of massive tumour invasion. In contrast, slow progressive liver failure due to cirrhosis kills wtER-α-positive HCC patients. Based on this finding, Villa et al. proposed that the treatment for wtER-α HCC patients should focus on chronic liver failure [36, 41]. Furthermore, vER-α in chronic hepatitis and cirrhosis is also associated with high levels of oxidative stress-induced DNA damage and c-myc expression [42].

Recently, hypomethylation of the long interspersed nuclear element-1 (LINE-1) promoter was reported to correlate with poor outcomes of HCC [43]. Before this finding, LINE-1 hypomethylation was more frequently observed in hepatitis-related HCC to be accompanied by methylation of the ER promoter [44, 45]. This hypermethylation of CpG islands in wtER genes may partially contribute to the significant downregulation of wtER and upregulation of vER-α in HCC [46]. The mechanism by which the expression pattern of the ER-α subtype is changed during liver tumourigenesis remains largely unknown. With more conclusive evidence, the expression pattern of the ER-α subtypes could serve as a potential prognostic indicator for HCC and provide a novel target for HCC treatment.

Anti-inflammation effects of estrogen

The multitasking role of estrogen in inflammation is dependent on its concentration, cell type and context, and the anti-inflammation effect of estrogen has been further confirmed in many disease models, including liver disease. If B cell-dependent immunity or an overshooting fibrotic tissue repair process does not play a central role, estrogen would have a protective effect in chronic inflammatory diseases [47]. Some cytokines contribute to the occurrence of liver disease, and possible effects of estrogen on the release of proinflammatory cytokines in vitro have been discussed in a previous review (Table 2) [47].

Table 2 Summary of possible effects of estrogen on cytokine production in vitro

Moreover, estrogen could inhibit the NF-κB pathway and block the expression of adhesion molecules. Inflammation factors, such as nitric oxide (NO) and reactive oxygen species (ROS) production are also downregulated in inflammation milieus. Given the emerging concept of cancer-related inflammation, it is of scientific and clinical interest to explore the possibility of using the anti-inflammation effect of estrogen in HCC prevention.

IL-6 inhibition by estrogen

Hepatoma has been considered an inflammation-related cancer caused by chronic hepatitis [5961]. During chronic inflammation, proinflammatory cytokines and immune cells create a tumour microenvironment that influences hepatocarcinogenesis. Among these, IL-6 is believed to be a key component in inflammation-associated tumourigenesis [6264]. More importantly, estrogen has a significant impact on the production of IL-6. Preliminary studies showed that elevated IL-6 expression was associated with a high rate of metastasis and poor prognosis in HCC [6365]. Concordant evidence from Naugler’s group showed that MyD88-dependent production of IL-6 contributed to gender disparity of HCC because IL-6 ablation protected male mice from HCC and that estrogen inhibited IL-6 production [51].

In the liver, the release of IL-6 from Kupffer cells (KCs) is modulated by MyD88-dependent NF-κB signaling, whose activation is triggered by IL-1α from dying hepatocytes [6668]. According to the report by Naugler et al., E2 treatment could reduce diethylnitrosamine (DEN)-induced liver injury by inhibiting IL-6 production from KCs [51]. Moreover, E2 also provides protection in IL-6-treated mice, which suggests that E2 may inhibit downstream IL-6 signalling. The inhibition of the IL-6 promoter activity through inactivation of NF-κB and C/EBPβ causes downregulation of IL-6 [69]. These studies provide promising evidence for the higher incidence of HCC in males than females based on the role of IL-6 in anti-inflammatory effects [70]. However, a recent study on Forkhead box A (Foxa)-deficient mice showed that the IL-6 level did not correlate with tumour load when Foxa1/2 were only ablated in hepatocytes [71]. However, inflammatory monocytes that were recruited from circulation after HCC initiation exerted multiple effects on the tumour microenvironment. During HCC progression, tumour-associated macrophages (TAMs) replace KCs as the dominant modulator [61]. Taken together, these findings suggest that IL-6 is one of the regulators involved in the sexual dimorphism of HCC.

Effects of estrogen on STAT3 activity

Signal transducer and activator of transcription-3 (STAT3) has been identified as a key regulator of macrophage functions and is involved in several programmes related to tumour progression [7275]. Moreover, STAT3 signalling is a central signalling hub in cancer-related inflammation. The inflammatory microenvironment is orchestrated by numerous cytokines, chemokines and other mediators, and STAT3 is critical in regulating these inflammatory factors, such as IL-6, macrophage colony-stimulating factor, prostaglandin and cyclooxygenase-2 [76]. In STAT3-deficient mice, the liver tumour load caused by DEN treatment was significantly reduced [77]. In addition, the JAK/STAT3 pathway was enhanced in suppressor of cytokine signalling-3 (SOCS3) knockout mice, which were sensitive to hepatitis-induced hepatocarcinogenesis [78]. STAT3 signalling is negatively regulated through feedback loops. However, the polarization of macrophages to the M2 phenotype disturbs this homeostasis and keeps STAT3 activated; this, in turn, attenuates anti-tumour immune responses [79].

Recently, Hou et al. found that ER-α could suppress STAT3 activity in HCC cell lines and tumour tissues by elevating the expression of protein tyrosine phosphatase receptor type O (PTPRO) in female mice [80]. In E2-treated mice, an increased PTPRO level significantly inhibited HCC. Mechanistically, ER-α binds to EREs on the promoter of PTPRO then increases its expression. Moreover, it was found that the promoter region is methylated, which inactivates the PTPRO gene in HCC in human and rat models [81, 82]. Methylation-mediated silencing of suppressor genes promotes carcinogenesis [83, 84], but the methylation of ptpro that is modulated by ER-α must still be confirmed. In addition, this group found that PTPRO dephosphorylated STAT3 at Y705 and S727 then attenuated STAT3 signalling. Therefore, we could conclude that ER-α regulates STAT3 signalling by inhibiting IL-6 before STAT3 activation and directly suppressing STAT3 activity through PTPRO activation.

Recruitment of ER-α depends on FOXA1/2

To exert multiple functions of estrogen, a ligand-bound ER must recognize ERE in target promoters. Previous studies have shown Foxa1/2 are involved in liver development and biological activity [8588]. Additionally, in breast and prostate, the recruitment of ER-α and androgen receptor (AR) to target genes depends on FOXA1 [8991]. No protective effect of estrogen could be observed in FOXA-deficient mice, and ER-α and AR exerted protective and oncogenic functions in HCC in a FOXA1/2-dependent manner [71]. According to this work, ER-α and AR are recruited to their target genes with assistance from FOXA1/2, and an ERE/ARE is found to be adjacent to FOXA binding sites on promoters. Moreover, an abundance of single nucleotide polymorphisms (SNPs) of the FOXA2 binding site is found on target genes during HCC progression in women due to attenuated affinity of FOXA2 and ER-α for their targets. In their study, estrogen was also found to enhance liver injury in mutant mice. In addition, genotoxic metabolites from estrogen contribute to carcinogenesis [92], hence, raising the notion that estrogen action in the liver is determined by the overall cellular context, rather than the hormone itself.

Some microRNAs promote HCC through inhibiting ER-α

Previous studies found that miR-22 was downregulated in HCC and considered as a suppressor of cell proliferation [93]. However, Jiang et al. found that miR-22 was highly expressed in male HCC tumour adjacent tissue, and this expression was correlated with decreased ERα expression [66]. Furthermore, they showed that miR-22 inhibited ER-α transcription by directly targeting its 3′-UTR region, which was consistent with a previous study [94]. The deprivation of the anti-tumour effect of ER-α caused by miR-22 led to the carcinogenic process of adjacent liver tissues. Intriguingly, miR-18a, which has a high expression pattern in HCC tumour tissues, was also found to suppress the transcription of the ER-α gene [95]. However, miR-18a was not an inducer of female benign hepatoma in their research, which supported the notion that HCC and benign hepatoma are caused by distinct mechanisms. Actually, malignant transformation of OCPs-induced hepatic adenoma made estrogen as a HCC-promoting factor in early clinical trials [10].

Another study raised the possibility that miR-26a could prevent hepatoma cell growth through the repression of ER-α [96]. However, the marked decrease of ER-α and miR-26a in HCC tumour tissues indicated that downregulation of ER-α in HCC is mediated by a complex cellular network and not only by miR-26a.

Role of ER-β in liver disease requires more investigation

ER-β shows strong anti-proliferative [97, 98] and anti-inflammatory properties [99], and it is detected more frequently in patients with chronic liver disease than those with HCC [32], which implicates a protective role of ER-β in liver disease. Moreover, it has been shown that ER-β is overexpressed in HCV-related HCC tissues, but not in HBV-related tissues [100], suggesting that different mechanisms of HCC progression are induced by HCV and HBV. However, previous work showed the HBsAg could upregulate ER-β in HBsAg transgenic male mice, which raises the possibility that HBV infection may contribute to the gender disparity of HCC [101]. Intriguingly, ER-β displays anti-tumour effects in intrahepatic cholangiocarcinoma (IHCC) [102]. We believe that a better understanding of the roles of ER-β in liver disease will yield opportunities to develop novel therapies.

TAMs define an invasive microenvironment to promote tumour progression through multiple signalling pathways [103, 104]. M2-polarised TAMs promote angiogenesis, metastasis and immune suppression by the secretion and modulation of cytokines, chemokines and growth factors [61]. A recent report revealed that the inhibition of the JAK/STAT6 pathway reduced TAMs polarization, thus suppressing HCC growth [105]. Such an effect is specifically caused by ER-β-induced SOCS1 expression. This finding indicates the protective role of estrogen through ER-β binding, but intriguingly, ER-β restrains the progression and metastasis of hepatoma [105]. In addition, unliganded ER-β regulates three classes of genes, whereas ER-α must be ligand-bound to regulate its target genes [106]. These findings provide novel insights into the role of ER-β in liver cancer. Unfortunately, the function of ER-β in HCC is largely unclear and requires further investigation.

The synthesis of estrogen by aromatase in HCC

Elevated aromatase expression has been detected in hepatitis and HCC [107109]. Intratumoural aromatase is considered a key inducer of estrogen-dependent neoplasm, such as breast, endometrial, and surface epithelial-stromal ovarian carcinomas [110]. The aromatase inhibitor fadrozole hydrochloride was demonstrated to counter spontaneous HCC in rats [111]. However, the contribution made by aromatase to the tumour microenvironment has not yet clarified. The elevated activity and expression of aromatase was detected in malignant human liver tissues and cells [108], and the influence of polymorphisms of the CYP19 (aromatase) promoter is associated with risk for HCC [112]. However, no conclusive evidence could be found to mechanistically link local estrogen production to HCC development. Consistent with the notion that estrogen prevents HCC by anti-inflammation effect, aromatase was found to be a risk factor only in non-viral hepatitis-related HCC.


The effect of estrogen in HCC has turned from an oncogenic to protective role based on recent discoveries. Androgen promotes the development of liver and prostate cancer [113, 114], whereas estrogen plays an oppositing role in the development of breast cancer and HCC [51, 115, 116]. How does such an antagonism exist? Pioneer work on this issue revealed that synthetic estrogen might promote liver carcinogenesis after DEN treatment in animal models [1519]. Indeed, the precedence of estrogen or DEN treatment seems to have opposite effects on HCC development. Administration of estrogen prior to carcinogenic events such as DEN treatment, is believed to protect the liver from HCC [28], and this phenomenon is supported by a human model because estrogen usually functions in females before HCC initiation. Another possible mechanism for the oncogenic effect of estrogen is illustrated in the DEN-treatment model, where the NF-κB pathway is inhibited in hepatocytes (not in KCs). Blockage of NF-κB signalling in DEN-treated hepatocytes promotes carcinogenesis, because hepatocytes suffer severe cell death through necrosis and apoptosis [67]. In contrast, the inhibition of NF-κB signalling has a suppressive effect in hepatocytes of Mdr2−/− mice, which is an inflammation-associated liver cancer model [68], consistent with the result in Huh7 cells [117]. Moreover, estrogen is found to attenuate HCC progression by regulating cell proliferation, invasion and apoptosis by inhibiting ER-α-induced NF-κB signalling [118]. NF-κB is highly associated with cancer-related inflammation, and estrogen inhibits NF-κB signalling; therefore, a novel model that fully captures the complex behavior of human HCC generation is required to understand the molecular mechanism by which the origin of HCC is modulated [119].

With emerging evidence supporting HCC as an inflammation-related cancer [59], we speculate that estrogen may, at least partially, play its protective role through its anti-inflammation effects. As described in detail in Figure 2, estrogen is involved in the regulation of the inflammation network in HCC by restraining of proinflammatory cytokines and inhibiting downstream signalling pathways. However, it is also reported that estrogen promotes hepatocytes proliferation [120]. Here, we believe that estrogen exerts promoting and inhibiting effects on HCC development, but, in tumour milieus, it is generally accepted as a mediator of anti-inflammation. The oncogenic effect of estrogen could also play a part in tumourigenesis, as cancer cells will use all of the help they can get. That is, both faces of estrogen are retained in HCC, but it protects females from HCC because inflammation is the key event for HCC development. The cellular milieus help estrogen protect from liver cancer. However, evidence for the anti-inflammatory effect of estrogen in HCC is limited; and uncovering how estrogen protects from HCC development would provide novel therapeutic approaches in drug design and cancer therapy (Table 3).

Figure 2

Estrogen inhibits HCC development through its anti-inflammatory effects. Estrogen exerts its protective effects through different pathways in KCs and hepatocytes. Ligand-bound ER-β inhibits M2 phenotype polarization in the ANA-1 cell line, and this procedure occurs mainly in TAMs, and not in KCs. Several miRNAs promote HCC by inhibiting ER-α. FOXA1/2 assists a ligand-bound ER-α to locate and bind to the ERE, and STAT3 plays a central role in these axes. Necrosis caused by liver injury defines the inflammatory microenvironment in the liver and eventually leads to HCC.

Table 3 Inhibition of inflammation factors by estrogen in HCC

It is important to bear in mind; however, that estrogen may cause some adverse effects in patients, especially in males, who form the majority of HCC cases. Therefore, the method for using hormone-related therapy to treat HCC requires rigorous testing and validation. In the future, finding the exact point at which estrogen switches its role from oncogenic to suppressive in HCC will enable us to establish a model to mimic chronic inflammation during HCC development.



Hepatocellular carcinoma


Estrogen receptor


Oral contraceptives


Estrogen response element


Wild type ER-α


Variant ER-α




Hepatitis B virus X protein


Hepatitis B surface antigen


Long interspersed nuclear element-1


Kupffer cells




Forkhead box A


Tumour-associated macrophages


Signal transducer and activator of transcription


Suppressor of cytokine signalling


protein tyrosine phosphatase receptor type O.


  1. 1.

    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322/caac.20107.

    PubMed  Google Scholar 

  2. 2.

    Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD: Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol. 2008, 14: 4300-4308. 10.3748/wjg.14.4300.

    PubMed Central  PubMed  Google Scholar 

  3. 3.

    Venook AP, Papandreou C, Furuse J, de Guevara LL: The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. Oncologist. 2010, 15 (Suppl 4): 5-13.

    PubMed  Google Scholar 

  4. 4.

    Lin S, Hoffmann K, Schemmer P: Treatment of hepatocellular carcinoma: a systematic review. Liver Cancer. 2012, 1: 144-158. 10.1159/000343828.

    PubMed Central  CAS  PubMed  Google Scholar 

  5. 5.

    Bruix J, Sherman M: Management of hepatocellular carcinoma: an update. Hepatology. 2011, 53: 1020-1022. 10.1002/hep.24199.

    PubMed Central  PubMed  Google Scholar 

  6. 6.

    Abou-Alfa GK: Sorafenib use in hepatocellular carcinoma: more questions than answers. Hepatology. 2014

    Google Scholar 

  7. 7.

    Bosch FX, Ribes J, Diaz M, Cleries R: Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004, 127: S5-S16. 10.1053/j.gastro.2004.09.011.

    PubMed  Google Scholar 

  8. 8.

    Kalra M, Mayes J, Assefa S, Kaul AK, Kaul R: Role of sex steroid receptors in pathobiology of hepatocellular carcinoma. World J Gastroenterol. 2008, 14: 5945-5961. 10.3748/wjg.14.5945.

    PubMed Central  CAS  PubMed  Google Scholar 

  9. 9.

    Ma WL, Hsu CL, Yeh CC, Wu MH, Huang CK, Jeng LB, Hung YC, Lin TY, Yeh S, Chang C: Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis. Hepatology. 2012, 56: 176-185.

    PubMed Central  CAS  PubMed  Google Scholar 

  10. 10.

    Giannitrapani L, Soresi M, La Spada E, Cervello M, D’Alessandro N, Montalto G: Sex hormones and risk of liver tumor. Ann N Y Acad Sci. 2006, 1089: 228-236. 10.1196/annals.1386.044.

    CAS  PubMed  Google Scholar 

  11. 11.

    De Maria N, Manno M, Villa E: Sex hormones and liver cancer. Mol Cell Endocrinol. 2002, 193: 59-63. 10.1016/S0303-7207(02)00096-5.

    CAS  PubMed  Google Scholar 

  12. 12.

    Pignata S, Daniele B, Gallo C, De Vivo R, Monfardini S, Perrone F: Endocrine treatment of hepatocellular carcinoma. Any evidence of benefit?. Eur J Cancer. 1998, 34: 25-32. 10.1016/S0959-8049(97)00317-1.

    CAS  PubMed  Google Scholar 

  13. 13.

    Farinati F, De Maria N, Marafin C, Fagiuoli S, Della LG, Naccarato R: Hepatocellular carcinoma in alcoholic cirrhosis: is sex hormone imbalance a pathogenetic factor?. Eur J Gastroenterol Hepatol. 1995, 7: 145-150.

    CAS  PubMed  Google Scholar 

  14. 14.

    Shimizu I, Yasuda M, Mizobuchi Y, Ma YR, Liu F, Shiba M, Horie T, Ito S: Suppressive effect of oestradiol on chemical hepatocarcinogenesis in rats. Gut. 1998, 42: 112-119. 10.1136/gut.42.1.112.

    PubMed Central  CAS  PubMed  Google Scholar 

  15. 15.

    Campen D, Maronpot R, Lucier G: Dose–response relationships in promotion of rat hepatocarcinogenesis by 17 alpha-ethinylestradiol. J Toxicol Environ Health. 1990, 29: 257-268. 10.1080/15287399009531389.

    CAS  PubMed  Google Scholar 

  16. 16.

    Yager JJ, Yager R: Oral contraceptive steroids as promoters of hepatocarcinogenesis in female Sprague–Dawley rats. Cancer Res. 1980, 40: 3680-3685.

    CAS  PubMed  Google Scholar 

  17. 17.

    Yager JD, Campbell HA, Longnecker DS, Roebuck BD, Benoit MC: Enhancement of hepatocarcinogenesis in female rats by ethinyl estradiol and mestranol but not estradiol. Cancer Res. 1984, 44: 3862-3869.

    CAS  PubMed  Google Scholar 

  18. 18.

    Cameron R, Imaida K, Ito N: Promotive effects of ethinyl estradiol in hepatocarcinogenesis initiated by diethylnitrosamine in male rats. Gann. 1981, 72: 339-340.

    CAS  PubMed  Google Scholar 

  19. 19.

    Wanless IR, Medline A: Role of estrogens as promoters of hepatic neoplasia. Lab Invest. 1982, 46: 313-320.

    CAS  PubMed  Google Scholar 

  20. 20.

    Fechner RE: Benign hepatic lesions and orally administered contraceptives. A report of seven cases and a critical analysis of the literature. Hum Pathol. 1977, 8: 255-268. 10.1016/S0046-8177(77)80022-1.

    CAS  PubMed  Google Scholar 

  21. 21.

    Vana J, Murphy GP, Aronoff BL, Baker HW: Primary liver tumors and oral contraceptives. Results of a survey. JAMA. 1977, 238: 2154-2158. 10.1001/jama.1977.03280210046019.

    CAS  PubMed  Google Scholar 

  22. 22.

    Di Maio M, De Maio E, Morabito A, D’Aniello R, De Feo G, Gallo C, Perrone F: Hormonal treatment of human hepatocellular carcinoma. Ann N Y Acad Sci. 2006, 1089: 252-261. 10.1196/annals.1386.007.

    CAS  PubMed  Google Scholar 

  23. 23.

    Maheshwari S, Sarraj A, Kramer J, El-Serag HB: Oral contraception and the risk of hepatocellular carcinoma. J Hepatol. 2007, 47: 506-513. 10.1016/j.jhep.2007.03.015.

    CAS  PubMed  Google Scholar 

  24. 24.

    Villa E, Dugani A, Moles A, Camellini L, Grottola A, Buttafoco P, Merighi A, Ferretti I, Esposito P, Miglioli L, Bagni A, Troisi R, De Hemptinne B, Praet M, Callea F, Manenti F: Variant liver estrogen receptor transcripts already occur at an early stage of chronic liver disease. Hepatology. 1998, 27: 983-988. 10.1002/hep.510270413.

    CAS  PubMed  Google Scholar 

  25. 25.

    Villa E, Dugani A, Fantoni E, Camellini L, Buttafoco P, Grottola A, Pompei G, De Santis M, Ferrari A, Manenti F: Type of estrogen receptor determines response to antiestrogen therapy. Cancer Res. 1996, 56: 3883-3885.

    CAS  PubMed  Google Scholar 

  26. 26.

    Tan CK, Chow PK, Findlay M, Wong C, Machin D: Use of tamoxifen in hepatocellular carcinoma: a review and paradigm shift. J Gastroenterol Hepatol. 2000, 15: 725-729. 10.1046/j.1440-1746.2000.02235.x.

    CAS  PubMed  Google Scholar 

  27. 27.

    Chow PK, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, Soo KC: High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial. Hepatology. 2002, 36: 1221-1226. 10.1053/jhep.2002.36824.

    CAS  PubMed  Google Scholar 

  28. 28.

    Villa E: Role of estrogen in liver cancer. Womens Health (Lond Engl). 2008, 4: 41-50. 10.2217/17455057.4.1.41.

    CAS  Google Scholar 

  29. 29.

    Yu MW, Chang HC, Chang SC, Liaw YF, Lin SM, Liu CJ, Lee SD, Lin CL, Chen PJ, Lin SC, Chen CJ: Role of reproductive factors in hepatocellular carcinoma: impact on hepatitis B- and C-related risk. Hepatology. 2003, 38: 1393-1400.

    PubMed  Google Scholar 

  30. 30.

    Shimizu I: Impact of oestrogens on the progression of liver disease. Liver Int. 2003, 23: 63-69. 10.1034/j.1600-0676.2003.00811.x.

    CAS  PubMed  Google Scholar 

  31. 31.

    El-Serag HB, Mason AC, Key C: Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology. 2001, 33: 62-65. 10.1053/jhep.2001.21041.

    CAS  PubMed  Google Scholar 

  32. 32.

    Iavarone M, Lampertico P, Seletti C, Francesca DM, Ronchi G, Del NE, Colombo M: The clinical and pathogenetic significance of estrogen receptor-beta expression in chronic liver diseases and liver carcinoma. Cancer. 2003, 98: 529-534. 10.1002/cncr.11528.

    CAS  PubMed  Google Scholar 

  33. 33.

    Barone I, Brusco L, Fuqua SA: Estrogen receptor mutations and changes in downstream gene expression and signaling. Clin Cancer Res. 2010, 16: 2702-2708. 10.1158/1078-0432.CCR-09-1753.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. 34.

    Miceli V, Cocciadiferro L, Fregapane M, Zarcone M, Montalto G, Polito LM, Agostara B, Granata OM, Carruba G: Expression of wild-type and variant estrogen receptor alpha in liver carcinogenesis and tumor progression. OMICS. 2011, 15: 313-317. 10.1089/omi.2010.0108.

    CAS  PubMed  Google Scholar 

  35. 35.

    Villa E, Camellini L, Dugani A, Zucchi F, Grottola A, Merighi A, Buttafoco P, Losi L, Manenti F: Variant estrogen receptor messenger RNA species detected in human primary hepatocellular carcinoma. Cancer Res. 1995, 55: 498-500.

    CAS  PubMed  Google Scholar 

  36. 36.

    Villa E, Moles A, Ferretti I, Buttafoco P, Grottola A, Del BM, De Santis M, Manenti F: Natural history of inoperable hepatocellular carcinoma: estrogen receptors’ status in the tumor is the strongest prognostic factor for survival. Hepatology. 2000, 32: 233-238. 10.1053/jhep.2000.9603.

    CAS  PubMed  Google Scholar 

  37. 37.

    Villa E, Colantoni A, Camma C, Grottola A, Buttafoco P, Gelmini R, Ferretti I, Manenti F: Estrogen receptor classification for hepatocellular carcinoma: comparison with clinical staging systems. J Clin Oncol. 2003, 21: 441-446. 10.1200/JCO.2003.11.051.

    CAS  PubMed  Google Scholar 

  38. 38.

    Han J, Ding L, Yuan B, Yang X, Wang X, Li J, Lu Q, Huang C, Ye Q: Hepatitis B virus X protein and the estrogen receptor variant lacking exon 5 inhibit estrogen receptor signaling in hepatoma cells. Nucleic Acids Res. 2006, 34: 3095-3106. 10.1093/nar/gkl389.

    PubMed Central  CAS  PubMed  Google Scholar 

  39. 39.

    Lee LM, Cao J, Deng H, Chen P, Gatalica Z, Wang ZY: ER-alpha36, a novel variant of ER-alpha, is expressed in ER-positive and -negative human breast carcinomas. Anticancer Res. 2008, 28: 479-483.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. 40.

    Villa E, Ferretti I, Grottola A, Buttafoco P, Buono MG, Giannini F, Manno M, Bertani H, Dugani A, Manenti F: Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors. Br J Cancer. 2001, 84: 881-885. 10.1054/bjoc.2000.1534.

    PubMed Central  CAS  PubMed  Google Scholar 

  41. 41.

    Barone C, Koeberle D, Metselaar H, Parisi G, Sansonno D, Spinzi G: Multidisciplinary approach for HCC patients: hepatology for the oncologists. Ann Oncol. 2013, 24 (Suppl 2): i15-i23.

    Google Scholar 

  42. 42.

    Farinati F, Cardin R, Bortolami M, Grottola A, Manno M, Colantoni A, Villa E: Estrogens receptors and oxidative damage in the liver. Mol Cell Endocrinol. 2002, 193: 85-88. 10.1016/S0303-7207(02)00100-4.

    CAS  PubMed  Google Scholar 

  43. 43.

    Gao XD, Qu JH, Chang XJ, Lu YY, Bai WL, Wang H, Xu ZX, An LJ, Wang CP, Zeng Z, Yang YP: Hypomethylation of long interspersed nuclear element-1 promoter is associated with poor outcomes for curative resected hepatocellular carcinoma. Liver Int. 2013, 34: 136-146.

    PubMed Central  Google Scholar 

  44. 44.

    Kim MJ, White-Cross JA, Shen L, Issa JP, Rashid A: Hypomethylation of long interspersed nuclear element-1 in hepatocellular carcinomas. Mod Pathol. 2009, 22: 442-449. 10.1038/modpathol.2008.203.

    CAS  PubMed  Google Scholar 

  45. 45.

    Hishida M, Nomoto S, Inokawa Y, Hayashi M, Kanda M, Okamura Y, Nishikawa Y, Tanaka C, Kobayashi D, Yamada S, Nakayama G, Fujii T, Sugimoto H, Koike M, Fujiwara M, Takeda S, Kodera Y: Estrogen receptor 1 gene as a tumor suppressor gene in hepatocellular carcinoma detected by triple-combination array analysis. Int J Oncol. 2013, 43: 88-94.

    CAS  PubMed  Google Scholar 

  46. 46.

    Shen L, Ahuja N, Shen Y, Habib NA, Toyota M, Rashid A, Issa JP: DNA methylation and environmental exposures in human hepatocellular carcinoma. J Natl Cancer Inst. 2002, 94: 755-761. 10.1093/jnci/94.10.755.

    CAS  PubMed  Google Scholar 

  47. 47.

    Straub RH: The complex role of estrogens in inflammation. Endocr Rev. 2007, 28: 521-574. 10.1210/er.2007-0001.

    CAS  PubMed  Google Scholar 

  48. 48.

    Rogers A, Eastell R: The effect of 17beta-estradiol on production of cytokines in cultures of peripheral blood. Bone. 2001, 29: 30-34. 10.1016/S8756-3282(01)00468-9.

    CAS  PubMed  Google Scholar 

  49. 49.

    Polan ML, Loukides J, Nelson P, Carding S, Diamond M, Walsh A, Bottomly K: Progesterone and estradiol modulate interleukin-1 beta messenger ribonucleic acid levels in cultured human peripheral monocytes. J Clin Endocrinol Metab. 1989, 69: 1200-1206. 10.1210/jcem-69-6-1200.

    CAS  PubMed  Google Scholar 

  50. 50.

    Kawasaki T, Ushiyama T, Inoue K, Hukuda S: Effects of estrogen on interleukin-6 production in rheumatoid fibroblast-like synoviocytes. Clin Exp Rheumatol. 2000, 18: 743-745.

    CAS  PubMed  Google Scholar 

  51. 51.

    Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M: Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007, 317: 121-124. 10.1126/science.1140485.

    CAS  PubMed  Google Scholar 

  52. 52.

    Rodriguez E, Lopez R, Paez A, Masso F, Montano LF: 17Beta-estradiol inhibits the adhesion of leukocytes in TNF-alpha stimulated human endothelial cells by blocking IL-8 and MCP-1 secretion, but not its transcription. Life Sci. 2002, 71: 2181-2193. 10.1016/S0024-3205(02)01999-9.

    CAS  PubMed  Google Scholar 

  53. 53.

    Kanda N, Watanabe S: 17beta-estradiol, progesterone, and dihydrotestosterone suppress the growth of human melanoma by inhibiting interleukin-8 production. J Invest Dermatol. 2001, 117: 274-283. 10.1046/j.1523-1747.2001.01422.x.

    CAS  PubMed  Google Scholar 

  54. 54.

    Gilmore W, Weiner LP, Correale J: Effect of estradiol on cytokine secretion by proteolipid protein-specific T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol. 1997, 158: 446-451.

    CAS  PubMed  Google Scholar 

  55. 55.

    Liu HY, Buenafe AC, Matejuk A, Ito A, Zamora A, Dwyer J, Vandenbark AA, Offner H: Estrogen inhibition of EAE involves effects on dendritic cell function. J Neurosci Res. 2002, 70: 238-248. 10.1002/jnr.10409.

    CAS  PubMed  Google Scholar 

  56. 56.

    Kanda N, Tamaki K: Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol. 1999, 103: 282-288. 10.1016/S0091-6749(99)70503-8.

    CAS  PubMed  Google Scholar 

  57. 57.

    Oursler MJ, Cortese C, Keeting P, Anderson MA, Bonde SK, Riggs BL, Spelsberg TC: Modulation of transforming growth factor-beta production in normal human osteoblast-like cells by 17 beta-estradiol and parathyroid hormone. Endocrinology. 1991, 129: 3313-3320. 10.1210/endo-129-6-3313.

    CAS  PubMed  Google Scholar 

  58. 58.

    Hatthachote P, Gillespie JI: Complex interactions between sex steroids and cytokines in the human pregnant myometrium: evidence for an autocrine signaling system at term. Endocrinology. 1999, 140: 2533-2540.

    CAS  PubMed  Google Scholar 

  59. 59.

    Berasain C, Perugorria MJ, Latasa MU, Castillo J, Goni S, Santamaria M, Prieto J, Avila MA: The epidermal growth factor receptor: a link between inflammation and liver cancer. Exp Biol Med (Maywood). 2009, 234: 713-725. 10.3181/0901-MR-12.

    CAS  Google Scholar 

  60. 60.

    Mantovani A, Allavena P, Sica A, Balkwill F: Cancer-related inflammation. Nature. 2008, 454: 436-444. 10.1038/nature07205.

    CAS  PubMed  Google Scholar 

  61. 61.

    Capece D, Fischietti M, Verzella D, Gaggiano A, Cicciarelli G, Tessitore A, Zazzeroni F, Alesse E: The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int. 2013, 2013: 187204-

    PubMed Central  PubMed  Google Scholar 

  62. 62.

    Prieto J: Inflammation, HCC and sex: IL-6 in the centre of the triangle. J Hepatol. 2008, 48: 380-381. 10.1016/j.jhep.2007.11.007.

    CAS  PubMed  Google Scholar 

  63. 63.

    Nakagawa H, Maeda S, Yoshida H, Tateishi R, Masuzaki R, Ohki T, Hayakawa Y, Kinoshita H, Yamakado M, Kato N, Shiina S, Omata M: Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences. Int J Cancer. 2009, 125: 2264-2269. 10.1002/ijc.24720.

    CAS  PubMed  Google Scholar 

  64. 64.

    Wong VW, Yu J, Cheng AS, Wong GL, Chan HY, Chu ES, Ng EK, Chan FK, Sung JJ, Chan HL: High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. Int J Cancer. 2009, 124: 2766-2770. 10.1002/ijc.24281.

    CAS  PubMed  Google Scholar 

  65. 65.

    Hsia CY, Huo TI, Chiang SY, Lu MF, Sun CL, Wu JC, Lee PC, Chi CW, Lui WY, Lee SD: Evaluation of interleukin-6, interleukin-10 and human hepatocyte growth factor as tumor markers for hepatocellular carcinoma. Eur J Surg Oncol. 2007, 33: 208-212. 10.1016/j.ejso.2006.10.036.

    PubMed  Google Scholar 

  66. 66.

    Jiang R, Deng L, Zhao L, Li X, Zhang F, Xia Y, Gao Y, Wang X, Sun B: miR-22 promotes HBV-related hepatocellular carcinoma development in males. Clin Cancer Res. 2011, 17: 5593-5603. 10.1158/1078-0432.CCR-10-1734.

    CAS  PubMed  Google Scholar 

  67. 67.

    Sun B, Karin M: NF-kappaB signaling, liver disease and hepatoprotective agents. Oncogene. 2008, 27: 6228-6244. 10.1038/onc.2008.300.

    CAS  PubMed  Google Scholar 

  68. 68.

    Karin M, Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005, 5: 749-759. 10.1038/nri1703.

    CAS  PubMed  Google Scholar 

  69. 69.

    Stein B, Yang MX: Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol Cell Biol. 1995, 15: 4971-4979.

    PubMed Central  CAS  PubMed  Google Scholar 

  70. 70.

    Lippitz BE: Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013, 14: e218-e228. 10.1016/S1470-2045(12)70582-X.

    CAS  PubMed  Google Scholar 

  71. 71.

    Li Z, Tuteja G, Schug J, Kaestner KH: Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell. 2012, 148: 72-83. 10.1016/j.cell.2011.11.026.

    PubMed Central  CAS  PubMed  Google Scholar 

  72. 72.

    Sica A, Allavena P, Mantovani A: Cancer related inflammation: the macrophage connection. Cancer Lett. 2008, 267: 204-215. 10.1016/j.canlet.2008.03.028.

    CAS  PubMed  Google Scholar 

  73. 73.

    Calvisi DF: Dr. Jekyll and Mr. Hyde: a paradoxical oncogenic and tumor suppressive role of signal transducer and activator of transcription 3 in liver cancer. Hepatology. 2011, 54: 9-12.

    CAS  PubMed  Google Scholar 

  74. 74.

    He G, Karin M: NF-kappaB and STAT3 - key players in liver inflammation and cancer. Cell Res. 2011, 21: 159-168. 10.1038/cr.2010.183.

    PubMed Central  CAS  PubMed  Google Scholar 

  75. 75.

    Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, Factor VM, Thorgeirsson SS: Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006, 130: 1117-1128. 10.1053/j.gastro.2006.01.006.

    CAS  PubMed  Google Scholar 

  76. 76.

    Fan Y, Mao R, Yang J: NF-kappaB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell. 2013, 4: 176-185. 10.1007/s13238-013-2084-3.

    CAS  PubMed  Google Scholar 

  77. 77.

    He G, Yu GY, Temkin V, Ogata H, Kuntzen C, Sakurai T, Sieghart W, Peck-Radosavljevic M, Leffert HL, Karin M: Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell. 2010, 17: 286-297. 10.1016/j.ccr.2009.12.048.

    PubMed Central  CAS  PubMed  Google Scholar 

  78. 78.

    Ogata H, Kobayashi T, Chinen T, Takaki H, Sanada T, Minoda Y, Koga K, Takaesu G, Maehara Y, Iida M, Yoshimura A: Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Gastroenterology. 2006, 131: 179-193. 10.1053/j.gastro.2006.04.025.

    CAS  PubMed  Google Scholar 

  79. 79.

    Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mule J, Kerr WG, Jove R, Pardoll D, Yu H: Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005, 11: 1314-1321. 10.1038/nm1325.

    CAS  PubMed  Google Scholar 

  80. 80.

    Hou J, Xu J, Jiang R, Wang Y, Chen C, Deng L, Huang X, Wang X, Sun B: Estrogen-sensitive PTPRO expression represses hepatocellular carcinoma progression by control of STAT3. Hepatology. 2013, 57: 678-688. 10.1002/hep.25980.

    CAS  PubMed  Google Scholar 

  81. 81.

    Motiwala T, Ghoshal K, Das A, Majumder S, Weichenhan D, Wu YZ, Holman K, James SJ, Jacob ST, Plass C: Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas. Oncogene. 2003, 22: 6319-6331. 10.1038/sj.onc.1206750.

    PubMed Central  CAS  PubMed  Google Scholar 

  82. 82.

    Hsu SH, Motiwala T, Roy S, Claus R, Mustafa M, Plass C, Freitas MA, Ghoshal K, Jacob ST: Methylation of the PTPRO gene in human hepatocellular carcinoma and identification of VCP as its substrate. J Cell Biochem. 2013, 114: 1810-1818. 10.1002/jcb.24525.

    PubMed Central  CAS  PubMed  Google Scholar 

  83. 83.

    Sceusi EL, Loose DS, Wray CJ: Clinical implications of DNA methylation in hepatocellular carcinoma. HPB (Oxford). 2011, 13: 369-376. 10.1111/j.1477-2574.2011.00303.x.

    Google Scholar 

  84. 84.

    Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA, Schroeder I, Factor VM, Thorgeirsson SS: Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest. 2007, 117: 2713-2722. 10.1172/JCI31457.

    PubMed Central  CAS  PubMed  Google Scholar 

  85. 85.

    Friedman JR, Kaestner KH: The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci. 2006, 63: 2317-2328. 10.1007/s00018-006-6095-6.

    CAS  PubMed  Google Scholar 

  86. 86.

    Sund NJ, Ang SL, Sackett SD, Shen W, Daigle N, Magnuson MA, Kaestner KH: Hepatocyte nuclear factor 3beta (Foxa2) is dispensable for maintaining the differentiated state of the adult hepatocyte. Mol Cell Biol. 2000, 20: 5175-5183. 10.1128/MCB.20.14.5175-5183.2000.

    PubMed Central  CAS  PubMed  Google Scholar 

  87. 87.

    Bochkis IM, Rubins NE, White P, Furth EE, Friedman JR, Kaestner KH: Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress. Nat Med. 2008, 14: 828-836. 10.1038/nm.1853.

    PubMed Central  CAS  PubMed  Google Scholar 

  88. 88.

    Kaestner KH: The FoxA factors in organogenesis and differentiation. Curr Opin Genet Dev. 2010, 20: 527-532. 10.1016/j.gde.2010.06.005.

    PubMed Central  CAS  PubMed  Google Scholar 

  89. 89.

    Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, Eeckhoute J, Shao W, Hestermann EV, Geistlinger TR, Fox EA, Silver PA, Brown M: Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell. 2005, 122: 33-43. 10.1016/j.cell.2005.05.008.

    CAS  PubMed  Google Scholar 

  90. 90.

    Gao N, Zhang J, Rao MA, Case TC, Mirosevich J, Wang Y, Jin R, Gupta A, Rennie PS, Matusik RJ: The role of hepatocyte nuclear factor-3 alpha (forkhead box A1) and androgen receptor in transcriptional regulation of prostatic genes. Mol Endocrinol. 2003, 17: 1484-1507. 10.1210/me.2003-0020.

    CAS  PubMed  Google Scholar 

  91. 91.

    Yu X, Gupta A, Wang Y, Suzuki K, Mirosevich J, Orgebin-Crist MC, Matusik RJ: Foxa1 and Foxa2 interact with the androgen receptor to regulate prostate and epididymal genes differentially. Ann N Y Acad Sci. 2005, 1061: 77-93. 10.1196/annals.1336.009.

    CAS  PubMed  Google Scholar 

  92. 92.

    Yager JD, Liehr JG: Molecular mechanisms of estrogen carcinogenesis. Annu Rev Pharmacol Toxicol. 1996, 36: 203-232. 10.1146/

    CAS  PubMed  Google Scholar 

  93. 93.

    Zhang J, Yang Y, Yang T, Liu Y, Li A, Fu S, Wu M, Pan Z, Zhou W: microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer. 2010, 103: 1215-1220. 10.1038/sj.bjc.6605895.

    PubMed Central  CAS  PubMed  Google Scholar 

  94. 94.

    Pandey DP, Picard D: miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA. Mol Cell Biol. 2009, 29: 3783-3790. 10.1128/MCB.01875-08.

    PubMed Central  CAS  PubMed  Google Scholar 

  95. 95.

    Liu WH, Yeh SH, Lu CC, Yu SL, Chen HY, Lin CY, Chen DS, Chen PJ: MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology. 2009, 136: 683-693. 10.1053/j.gastro.2008.10.029.

    CAS  PubMed  Google Scholar 

  96. 96.

    Chen L, Zheng J, Zhang Y, Yang L, Wang J, Ni J, Cui D, Yu C, Cai Z: Tumor-specific expression of microRNA-26a suppresses human hepatocellular carcinoma growth via cyclin-dependent and -independent pathways. Mol Ther. 2011, 19: 1521-1528. 10.1038/mt.2011.64.

    PubMed Central  CAS  PubMed  Google Scholar 

  97. 97.

    Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC: Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res. 2004, 64: 423-428. 10.1158/0008-5472.CAN-03-2446.

    CAS  PubMed  Google Scholar 

  98. 98.

    Strom A, Hartman J, Foster JS, Kietz S, Wimalasena J, Gustafsson JA: Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proc Natl Acad Sci U S A. 2004, 101: 1566-1571. 10.1073/pnas.0308319100.

    PubMed Central  PubMed  Google Scholar 

  99. 99.

    Cvoro A, Tatomer D, Tee MK, Zogovic T, Harris HA, Leitman DC: Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. J Immunol. 2008, 180: 630-636. 10.4049/jimmunol.180.1.630.

    CAS  PubMed  Google Scholar 

  100. 100.

    Wang AG, Lee KY, Kim SY, Choi JY, Lee KH, Kim WH, Wang HJ, Kim JM, Park MG, Yeom YI, Kim NS, Yu DY, Lee DS: The expression of estrogen receptors in hepatocellular carcinoma in Korean patients. Yonsei Med J. 2006, 47: 811-816. 10.3349/ymj.2006.47.6.811.

    PubMed Central  CAS  PubMed  Google Scholar 

  101. 101.

    Wang Y, Cui F, Lv Y, Li C, Xu X, Deng C, Wang D, Sun Y, Hu G, Lang Z, Huang C, Yang X: HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice. Hepatology. 2004, 39: 318-324. 10.1002/hep.20076.

    CAS  PubMed  Google Scholar 

  102. 102.

    Marzioni M, Torrice A, Saccomanno S, Rychlicki C, Agostinelli L, Pierantonelli I, Rhonnstad P, Trozzi L, Apelqvist T, Gentile R, Candelaresi C, Fava G, Semeraro R, Benedetti A, Gaudio E, Franchitto A, Onori P, De Minicis S, Carpino G, Kallin E, Alvaro D, Nilsson S: An oestrogen receptor beta-selective agonist exerts anti-neoplastic effects in experimental intrahepatic cholangiocarcinoma. Dig Liver Dis. 2012, 44: 134-142. 10.1016/j.dld.2011.06.014.

    CAS  PubMed  Google Scholar 

  103. 103.

    Condeelis J, Pollard JW: Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006, 124: 263-266. 10.1016/j.cell.2006.01.007.

    CAS  PubMed  Google Scholar 

  104. 104.

    Bingle L, Brown NJ, Lewis CE: The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002, 196: 254-265. 10.1002/path.1027.

    CAS  PubMed  Google Scholar 

  105. 105.

    Yang W, Lu Y, Xu Y, Xu L, Zheng W, Wu Y, Li L, Shen P: Estrogen represses hepatocellular carcinoma (HCC) growth via inhibiting alternative activation of tumor-associated macrophages (TAMs). J Biol Chem. 2012, 287: 40140-40149. 10.1074/jbc.M112.348763.

    PubMed Central  CAS  PubMed  Google Scholar 

  106. 106.

    Vivar OI, Zhao X, Saunier EF, Griffin C, Mayba OS, Tagliaferri M, Cohen I, Speed TP, Leitman DC: Estrogen receptor beta binds to and regulates three distinct classes of target genes. J Biol Chem. 2010, 285: 22059-22066. 10.1074/jbc.M110.114116.

    PubMed Central  CAS  PubMed  Google Scholar 

  107. 107.

    Harada N, Ota H, Yoshimura N, Katsuyama T, Takagi Y: Localized aberrant expression of cytochrome P450 aromatase in primary and metastatic malignant tumors of human liver. J Clin Endocrinol Metab. 1998, 83: 697-702.

    CAS  PubMed  Google Scholar 

  108. 108.

    Castagnetta LA, Agostara B, Montalto G, Polito L, Campisi I, Saetta A, Itoh T, Yu B, Chen S, Carruba G: Local estrogen formation by nontumoral, cirrhotic, and malignant human liver tissues and cells. Cancer Res. 2003, 63: 5041-5045.

    CAS  PubMed  Google Scholar 

  109. 109.

    Granata OM, Cocciadifero L, Campisi I, Miceli V, Montalto G, Polito LM, Agostara B, Carruba G: Androgen metabolism and biotransformation in nontumoral and malignant human liver tissues and cells. J Steroid Biochem Mol Biol. 2009, 113: 290-295. 10.1016/j.jsbmb.2009.01.013.

    CAS  PubMed  Google Scholar 

  110. 110.

    Sasano H, Harada N: Intratumoral aromatase in human breast, endometrial, and ovarian malignancies. Endocr Rev. 1998, 19: 593-607.

    CAS  PubMed  Google Scholar 

  111. 111.

    Gunson DE, Steele RE, Chau RY: Prevention of spontaneous tumours in female rats by fadrozole hydrochloride, an aromatase inhibitor. Br J Cancer. 1995, 72: 72-75. 10.1038/bjc.1995.279.

    PubMed Central  CAS  PubMed  Google Scholar 

  112. 112.

    Koh WP, Yuan JM, Wang R, Govindarajan S, Oppenheimer R, Zhang ZQ, Yu MC, Ingles SA: Aromatase (CYP19) promoter gene polymorphism and risk of nonviral hepatitis-related hepatocellular carcinoma. Cancer. 2011, 117: 3383-3392. 10.1002/cncr.25939.

    PubMed Central  CAS  PubMed  Google Scholar 

  113. 113.

    Paulson DF: Carcinoma of the prostate: the therapeutic dilemma. Annu Rev Med. 1984, 35: 341-372. 10.1146/

    CAS  PubMed  Google Scholar 

  114. 114.

    Smolev JK, Coffey DS, Scott WW: Experimental models for the study of prostatic adenocarcinoma. J Urol. 1977, 118: 216-220.

    CAS  PubMed  Google Scholar 

  115. 115.

    Hollingsworth AB, Lerner MR, Lightfoot SA, Wilkerson KB, Hanas JS, McCay PB, Brackett DJ: Prevention of DMBA-induced rat mammary carcinomas comparing leuprolide, oophorectomy, and tamoxifen. Breast Cancer Res Treat. 1998, 47: 63-70. 10.1023/A:1005872132373.

    CAS  PubMed  Google Scholar 

  116. 116.

    Zumoff B: Does postmenopausal estrogen administration increase the risk of breast cancer? Contributions of animal, biochemical, and clinical investigative studies to a resolution of the controversy. Proc Soc Exp Biol Med. 1998, 217: 30-37. 10.3181/00379727-217-44202.

    CAS  PubMed  Google Scholar 

  117. 117.

    Qiao L, Zhang H, Yu J, Francisco R, Dent P, Ebert MP, Rocken C, Farrell G: Constitutive activation of NF-kappaB in human hepatocellular carcinoma: evidence of a cytoprotective role. Hum Gene Ther. 2006, 17: 280-290. 10.1089/hum.2006.17.280.

    CAS  PubMed  Google Scholar 

  118. 118.

    Xu H, Wei Y, Zhang Y, Xu Y, Li F, Liu J, Zhang W, Han X, Tan R, Shen P: Oestrogen attenuates tumour progression in hepatocellular carcinoma. J Pathol. 2012, 228: 216-229. 10.1002/path.4009.

    CAS  PubMed  Google Scholar 

  119. 119.

    Francavilla A, Polimeno L, Barone M, Azzarone A, Starzl TE: Hepatic regeneration and growth factors. J Surg Oncol Suppl. 1993, 3: 1-7.

    PubMed Central  CAS  PubMed  Google Scholar 

  120. 120.

    Kalaitzidis D, Gilmore TD: Transcription factor cross-talk: the estrogen receptor and NF-kappaB. Trends Endocrinol Metab. 2005, 16: 46-52. 10.1016/j.tem.2005.01.004.

    CAS  PubMed  Google Scholar 

  121. 121.

    Harnish DC, Scicchitano MS, Adelman SJ, Lyttle CR, Karathanasis SK: The role of CBP in estrogen receptor cross-talk with nuclear factor-kappaB in HepG2 cells. Endocrinology. 2000, 141: 3403-3411.

    CAS  PubMed  Google Scholar 

Download references


This work was supported by National Natural Science Foundation of China (81201942). We thank Yongjie Yin for his help in figure preparation and Anyong Xie for reading the manuscript and making corrections.

Author information



Corresponding author

Correspondence to Xiujun Cai.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

LS performed article searches, drafted the manuscript and figures and revised the manuscript. YF performed language correction and contributed to refinement of the manuscript. HL and RM participated in information updating and viewpoint complementarity. XC provided the original idea, administrative support and financial support. All authors read and approved the final manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( ) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Cite this article

Shi, L., Feng, Y., Lin, H. et al. Role of estrogen in hepatocellular carcinoma: is inflammation the key?. J Transl Med 12, 93 (2014).

Download citation


  • Estrogen
  • Estrogen receptor
  • Hepatocellular carcinoma
  • Inflammation