Androgen-Receptor Gene CAG Repeats, Plasma Testosterone Levels, and Risk of Hepatitis B-Related Hepatocellular Carcinoma

Yu, Miao; Cheng, Shu Wen; Lin, Ming; Yang, Shan; Liaw, Yun Fan; Chang, Hsien-Chih; Hsiao, Tun Jen; Lin, Shu-Fu; Lee, Shou Dong; Chen, Pei‐Jer; Liu, Chun‐Jen; Chen, Chien Jen

doi:10.1093/jnci/92.24.2023

Cited by 132 publications

(128 citation statements)

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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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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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“…Both higher androgen levels and more active androgen receptor (AR) gene alleles correlated with an increased risk of HCC among male hepatitis B surface antigen (HBsAg) carriers. 5,6 In AR knockout mice, the development of chemically induced HCC was delayed and the mice had fewer tumors. 7 These studies indicate that the AR axis is involved in hepatocarcinogenesis, and an active AR pathway may augment HCC risk.…”

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confidence: 99%

Identification of androgen response elements in the enhancer I of hepatitis B virus: A mechanism for sex disparity in chronic hepatitis B #

et al. 2009

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Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) occurs more often in men than in women. Male HBV carriers usually have higher viral loads, which is a well-known risk factor for HCC. Whether and how the male androgen axis regulates HBV transcription and replication is investigated here. We used HBV transgenic mice to evaluate any sex disparity of serum hepatitis B surface antigen and HBV titers as well as the castration effect on this disparity. Compared to females, HBV transgenic male mice showed higher hepatitis B surface antigen and viral titers, which were lessened by castration of the males. In a cell culture system, HepG2 cells transfected with HBV and androgen receptor (AR) constructs were used to study the effect of the androgen pathway on viral transcription and replication. H epatitis B virus (HBV) chronically infects more than 350 million people worldwide and is a major risk factor for the development of liver cirrhosis and hepatocellular carcinoma (HCC). 1 The prevalence of chronic HBV infection in children has declined (Ͼ90%) following universal immunization. 2 However, adult HBV carriers still have a significant risk for HCC, especially those in areas where HBV infection is endemic. Investigation of mechanisms of HBV infection for HCC may discover new approaches to reduce the risk.Large cohort studies have identified risk factors for HBVrelated HCC, including old age, higher viral titer, diabetes, familial history of HCC, and the male sex. 3,4 The mechanisms of male susceptibility to HCC after HBV infection have been an important topic for study. Both higher androgen levels and more active androgen receptor (AR) gene alleles correlated with an increased risk of HCC among male hepatitis B surface antigen (HBsAg) carriers. 5,6 In AR knockout mice, the development of chemically induced HCC was delayed and the mice had fewer tumors. 7 These studies indicate that the AR axis is involved in hepatocarcinogenesis, and an active AR pathway may augment HCC risk. Consistent with this, we recently showed that HBV X protein (HBx) can enhance the transcriptional activity of AR in a ligand concentration-dependent manner, which may explain the male predominance of HBV-related HCC. 8 Because of the

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“…Both clinical observations and laboratory investigations have suggested that HCC is a sex hormone-dependent tumor, namely its male predominance (10), an apparent relationship to steroid hormones (11,12) and the altered status of sex hormone receptors (13,14). New therapeutic approaches with hormonal agents have thus been attempted in the treatment of HCC.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Megestrol Acetate on Growth of HepG2 Cells In vitro and In vivo

Zhang¹,

Chow

2004

Clinical Cancer Research

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Purpose: Hepatocellular carcinoma (HCC) is generally considered as a sex hormone-dependent tumor, and hormonal therapy has been proposed as a strategy for the treatment of HCC. The aim of the study is to investigate the effect of megestrol acetate, a synthetic progesteronal agent, on growth of HepG2 cells in vitro and in vivo.Experimental Design: Cell growth in vitro was assessed by a colormetric method, and cell growth in vivo was assessed by tumor volumetrics. Results: Megestrol acetate was shown to inhibit the growth of HepG2 cells in vitro in dose-and time-dependent manners with an IC 50 of 260 M (24-h incubation).The growth of HepG2 cell-transplanted tumors in nude mice was also inhibited by i.p. injection of megestrol acetate (10 mg/ kg/day). The tumor volumes of the megestrol acetate-treated group regressed to 59% of controls by week 6 and to 41% of controls by week 13. Apoptosis following G 1 arrest was observed in megestrol acetate-treated cells and may be a mechanism through which megestrol acetate inhibits HepG2 cells. Megestrol acetate was also demonstrated to have a beneficial effect on the weight gain of tumor-bearing nude mice, and the mean weight of the megestrol acetate-treated animals was higher than that of controls from week 4 of the treatment period, and the differences were statistically significant in week 5 and 6 (P < 0.05, compared with controls). No significant survival advantage was, however, demonstrated in the treatment group.Conclusions: This study showed that megestrol acetate inhibited the growth of HepG2 cells grown in vitro and in vivo. These data provide useful information for clinical study of megestrol acetate for the treatment of HCC.

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Androgen-Receptor Gene CAG Repeats, Plasma Testosterone Levels, and Risk of Hepatitis B-Related Hepatocellular Carcinoma

Abstract: Higher levels of androgen signaling, reflected by higher testosterone levels and 20 or fewer AR-CAG repeats, may be associated with an increased risk of HBV-related HCC in men.

Cited by 132 publications

References 24 publications

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

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

Identification of androgen response elements in the enhancer I of hepatitis B virus: A mechanism for sex disparity in chronic hepatitis B #

The Effect of Megestrol Acetate on Growth of HepG2 Cells In vitro and In vivo

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