Hormonal Markers and Hepatitis B Virus-Related Hepatocellular Carcinoma Risk: a Nested Case-Control Study Among Men

Yu, Ming‐Whei; Yang, Yuching; Yang, Shi-Yi; Cheng, Shuwen; Liaw, Yun–Fan; Lin, Shi‐Ming; Chen, Chien‐Jen

doi:10.1093/jnci/93.21.1644

Cited by 146 publications

(124 citation statements)

References 33 publications

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“…HCC is more prevalent in men subjects than it is in female subjects (Yu et al, 2001). The carcinogenesis of original HepG2 cells and BEL cells are significantly different in vitro and in vivo (Figure 2 and Table 1) because of differential AR expression on the cells (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…Hepatocellular carcinoma (HCC) is the fifth most common malignancy with a striking higher prevalence in men subjects than in women subjects throughout the world (Yu et al, 2001). Endocrinological and epidemiological studies indicate that HCC has a significantly higher concentration of androgen receptor (AR) than the surrounding liver tissue (Nagasue et al, 1995), and is an androgen-dependent tumor.…”

Section: Introductionmentioning

confidence: 99%

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Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells

Xiong

Chen

et al. 2007

Oncogene

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The molecular mechanism of striking higher prevalence of hepatocellular carcinoma (HCC) in male subjects has not yet been fully elucidated. Here, we report that androgen receptor (AR) is differentially expressed in different HCC cell lines. AR agonist dihydrotestosterone (DHT) enhances HCC cell growth and apoptotic resistance. Antagonist flutamide (FLU) blocks the effects of DHT on the HCC cell lines. Paternally expressed gene 10 (PEG10) is expressed in HCC cell lines at substantial high level. Using small interfering RNAs against AR and PEG10 in AR-and PEG10-expressing BEL-7404 hepatoma cells and HuH7 hepatoma cells (HuH7) cells, and AR-transfection technique in AR-lacking and PEG10-expressing HepG2 cells, we have confirmed that through upregulation and activation of PEG10, DHT enhances HCC cell growth and apoptotic resistance. We have further demonstrated that DHT upregulates expression of human telomerase reverse transcriptase (hTERT) in HCC cell lines in a PEG10-dependent manner. Moreover, AR directly interacts in vivo with androgen-responsive elements in the regions of promoter and exon 2 of PEG10 gene in HCC cell lines. DHT promotes the hepatoma formation in vivo nude mice through PEG10 activation. AR antagonists (FLU and valproate) inhibit the hepatoma formation. These findings suggest that PEG10 plays an essential role in hepatocarcinogenesis. The PEG10 inhibition can be a novel approach for therapy of HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells

Xiong

Chen

et al. 2007

Oncogene

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“…However, the male/female ratio of B-HCC patients was 6.4, which is much higher than that the 1.7 male/ female ratio of C-HCC patients. Sex hormone levels have been implicated in relation to hepatocarcinogenesis, 27,28 this might partially explain why B-HCC occurs predominantly in men. Because the majority of B-HCC was male, there were relative few female B-HCC patients.…”

Section: Discussionmentioning

confidence: 99%

Secular trends and geographic variations of hepatitis B virus and hepatitis C virus‐associated hepatocellular carcinoma in Taiwan

Yang

et al. 2006

Intl Journal of Cancer

124

128

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Etiological variations in hepatocellular carcinoma (HCC) exist across different geographic areas. To gain better control of HCC, we retrospectively studied the secular trends and geographic variations in hepatitis B virus (HBV)-related and hepatitis C virus (HCV)-related HCCs in Taiwan. A total of 18,423 HCC cases enrolled in 8 medical centers from 1981 to 2001 were reviewed. Overall, 67% of male HCC in Taiwan was related to HBV infection whereas 55.2% of female HCC in Taiwan was related to HCV infection. The mean age of patients with HBV-related HCC was 53.2 6 13.6 years, while the mean age of patients with HCV-related HCC was 65.1 6 9.1 years (p < 0.001). The male/female ratio was 6.4 for HBV-related HCC, while it was 1.7 for the HCV-related HCC (p < 0.001). The percentage of HBV-related HCC progressively decreased from 81.5 to 66.2% in males, and from 66.7 to 41.4% in females over the study period. Our study demonstrates that the percentage of HBV-related HCC has progressively decreased over the last 20 years. The relative decrease in HBV-related HCC was not due to a decrease in HBV-related HCC death. Instead, it was caused by an increase in HCV-related HCC. Prevention of new HCV infection and the treatment of chronic hepatitis C should be the primary goals, which will result in better control of HCC in the future, even in an HBV-endemic area like Taiwan. ' 2006 Wiley-Liss, Inc.Key words: hepatocellular carcinoma; hepatitis B virus; hepatitis C virus; secular trend; geographic variation; Taiwan Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, especially in sub-Saharan Africa and Southeast Asia. Since 1984, it has been the leading cause of cancer death in Taiwan, 1 accounting for approximately 7,000 death annually. In addition, around 8,000 new HCC cases are diagnosed each year. 2 High-risk groups for HCC include patients chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), liver cirrhosis patients, and people with a family history of HCC. Chronic HBV and HCV infections are the 2 major etiologies of HCC in Taiwan. 3 About 15-20% of the general population in Taiwan are chronic carriers of hepatitis B surface antigen (HBsAg). 4 HBV carriers have a 20-to 98-fold increased risk of HCC, 5,6 especially among the hepatitis B e antigen (HBeAg)-positive group. 7 A recent prospective study has further confirmed that positivity for HBeAg is associated with an increased risk of HCC. 8 To combat HBV infection in Taiwan, a mass immunization program has been launched on July 1, 1984, aiming first at the prevention of perinatal mother-to-infant, chronic HBV infection. 9 This nationwide vaccination program has markedly decreased the HBV carrier rate 10 and childhood HBVrelated HCCs (B-HCCs). 11 An 80-85% decrease in HCC among Taiwanese adults up to 3-4 decades later is anticipated. 12 The prevalence of anti-HCV antibody (anti-HCV) is 2-4% among the general population of Taiwan, 13 while it ranges from 0.95 to 2.2% in Taiwanese blood donors. 13,14 The anti-HCV prevalen...

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“…The male predominance in HBV-related HCC is significantly higher than that of HCVrelated HCC, with a ratio of 5-7:1 vs. 2-3:1 (17, 18). Among male HBV carriers, those with a higher level of serum androgen and more active AR gene alleles have a significantly increased risk of HCC (19,20). However, these two factors have not been reported to contribute to the increased risk of HCV-related HCC.…”

Section: Persistent Hepatitis B Virus (Hbv) Infection Is a Major Riskmentioning

confidence: 99%

Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level

Chiu

Yeh

Chen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

132

120

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Persistent hepatitis B virus (HBV) infection is a major risk of hepatocellular carcinoma (HCC). One intriguing feature of HBVrelated HCC is the male predominance, with a male to female ratio of 5-7:1. This dominance has been attributed to the elevated androgen level and the enhanced androgen receptor (AR)-mediated activity in the host. How HBV infection and AR signaling modulate HCC is unknown. We investigated whether the HBV nonstructural protein, X protein (HBx) could cooperate with the AR signaling pathway to enhance carcinogenesis. We found that HBx increased the anchorage-independent colony-formation potency of AR in a nontransformed mouse hepatocyte cell line. We also found that HBx functioned as a positive transcriptional coregulator to increase AR-mediated transcriptional activity. This transcription enhancement was increased in the presence of androgen in a concentration-responsive manner, thus explaining a more prominent effect in males. HBx did not physically associate with ligand-bound AR in the nucleus, and it likely augmented AR activity by increasing the phosphorylation of AR through HBx-mediated activation of the c-Src kinase signaling pathway. Our study documents HBx as a previously undescribed class of noncellular positive coregulators for AR. The results reveal a mechanism for the vulnerability of males to microbial infections and the subsequent development of cancer.androgen-responsive element H epatocellular carcinoma (HCC) is one of the leading cancers in the world, with more than half a million deaths per year (1). Chronic hepatitis, caused by hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, is a major risk factor for the development of HCC (2). Another risk factor is the male gender. HCC occurs much more frequently in men than in women, with a male to female ratio ranging from 2:1 to 11:1 (3). Both animal and human studies support the importance of androgen signaling in determining the male preference of HCC (4-13). It was also noted that the expression and activation of androgen receptor (AR) is increased in the tumor tissues as well as in the surrounding nontumorous liver tissue of patients with HCC (14-16). Intriguingly, the gender preference of HCC differs between HBV-and HCV-related cases. The male predominance in HBV-related HCC is significantly higher than that of HCVrelated HCC, with a ratio of 5-7:1 vs. 2-3:1 (17, 18). Among male HBV carriers, those with a higher level of serum androgen and more active AR gene alleles have a significantly increased risk of HCC (19,20). However, these two factors have not been reported to contribute to the increased risk of HCV-related HCC. Thus, HBV infection might uniquely cooperate with androgen signaling to accelerate hepatocarcinogenesis, raising the possibility that certain HBV gene(s) could modulate AR signaling activity and HCC development.AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily (21,22). It consists of several functional domains individually responsible for the activities ...

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Hormonal Markers and Hepatitis B Virus-Related Hepatocellular Carcinoma Risk: a Nested Case-Control Study Among Men

Abstract: Pathways involving androgen signaling may affect the risk of HBV-related HCC among men.

Cited by 146 publications

References 33 publications

Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells

Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells

Secular trends and geographic variations of hepatitis B virus and hepatitis C virus‐associated hepatocellular carcinoma in Taiwan

Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level

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