Androgen Receptor and Hepatocellular Carcinoma
Tatsuo Kanda1*, Osamu Yokosuka1 and Masao Omata2,3
1Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
2Yamanashi Hospitals (Central and Kita) Organization, 1-1-1 Fujimi, Kofu-shi, Yamanashi (400-8506), Japan
3University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo (113-8655), Japan
- *Corresponding Author:
- Tatsuo Kanda
Associate Professor, Department of Gastroenterology and Nephrology
Chiba University, Graduate School of Medicine
1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Tel: +81-43-226 2086
E-mail: [email protected]
Received date: April 22, 2013; Accepted date: June 06, 2013; Published date: June 08, 2013
Citation: Kanda T, Yokosuka O, Omata M (2013) Androgen Receptor and Hepatocellular Carcinoma. J Gastroint Dig Syst S12:012. doi: 10.4172/2161-069X.S12-012
Copyright: © 2013 Kanda T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The androgen receptor (AR) exists in normal liver as well as in human hepatocellular carcinoma (HCC) tissues. Recent studies revealed that AR plays an important role in hepatitis B viral as well as hepatitis C viral hepatocarcinogenesis. The targeting of AR might be developed as a new therapeutic option against HCC. This article provides information regarding the association between AR and HCC.
Androgen receptor; Foxa; HBV; HCV; STAT3; VEGF
HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; HCC: Hepatocellular Carcinoma; AR: Androgen Receptor; DBD: DNA-Binding Domain; ARE: Androgen Response Element; LBD: Ligand-Binding Domain; VEGF: Vascular Endothelial Growth Factor; STAT3: Signal Transducer and Activator of Transcription-3; Foxa: Vertebrae Forkhead Box A
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most commonly implicated risk factors of hepatocellular carcinoma (HCC) [1-3]. Irrespective of its cause, gender differences also exist in its prevalence .
Androgen receptor (AR), belonging to nuclear receptors, is putatively involved in the development of cancers such as prostate cancer, HCC and pancreatic cancer [5-7]. Androgen as a ligand interacts with AR, leading to a suggested link between transcriptional control and physiology. AR is characterized by a central DNA-binding domain (DBD), which targets AR to specific DNA sequences known as androgen response elements (AREs). The C-terminal half of the receptor encompasses the ligand-binding domain (LBD), which possesses the essential property of androgen recognition and ensures both specificity and selectivity of the physical response: LBD can be thought of as a molecular switch that, upon binding with ligand, shifts the receptor to a transcriptionally active state [8-10].
ARE is present in regulatory elements on target genes such as vascular endothelial growth factor (VEGF) and transforming growth factor beta-1, and regulates the growth and proliferation of hepatocytes [11,12]. Sorafenib, a molecular-targeted agent that inhibits tumor cell proliferation and angiogenesis by inhibiting Raf serine-threonine kinase (MAPKK kinase, MAPKKK), and VEGF, platelet-derived growth factor beta (PDGF), fms-related tyrosine kinase 3 (FLT3), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (C-Kit) receptor tyrosine kinase, was approved for treatment of advanced HCC in Europe, USA, Japan and other countries [13,14]. A selective transforming growth factor beta-1 receptor inhibits phosphorylation of the beta 1 integrin intracytoplasmic tail, blocking invasion of HCC cells .
Nagasue et al. reported that HCC had a significantly higher concentration of androgen receptors than did the surrounding liver tissue . There are several reports concerning the expression of AR mRNA and AR protein in tumor and in non-tumor parts of liver, suggesting that AR plays an important role in hepatocarcinogenesis [6,16-35].
Androgen Receptor-Mediating Signaling in HCVrelated Hepatocarcinogenesis
HCV core protein, which has a size of ~20 kDa, is one of the structural proteins. It has been reported that HCV core protein is involved in hepatocarcinogenesis [36-42]. Expression of HCV core protein as well as HCV full-length protein leads to activation of the AR signaling pathway in the presence of androgen . Cell culture-grown HCV infection in human hepatocytes also augments AR-mediated signaling in the presence of androgen [43,44]. These results showed that HCV core protein might cross-talk with the AR signaling pathway for promotion of carcinogenesis.
Figure 1: Mechanism of androgen receptor (AR)-mediated hepatocarcinogenesis.
HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma;
AR, androgen receptor; VEGF, vascular endothelial growth factor; STAT3,
signal transducer and activator of transcription-3; Foxa, vertebrae forkhead
box A; GSK-3ß kinase, glycogen synthase kinase-3beta kinase. Bold arrow
indicates androgen response element (ARE).
Signal transducer and activator of transcription-3 (STAT3) is often constitutively phosphorylated and activated in human cancers and in transformed cell lines and is implicated in tumorigenesis . HCV core increased STAT3 phosphorylation both at Ser-727 and at Tyr-705, which in turn activates AR . HCV infection also enhances VEGF, one of the target genes of AR , and induces in vitro angiogenesis in the presence of androgen . HCV core protein could be an activator of AR in the male-dominant disease HCC.
Androgen Receptor-Mediating Signaling in HBVrelated Hepatocarcinogenesis
The male predominance in HBV-related HCC is significantly high, with a ratio of 5-7:1 . HBx is the only HBV nonstructural gene that functions as a multifunctional regulator modulating gene transcription, cell responses to genotoxic stress, protein degradation, apoptosis, and several signaling pathways [46-48]. HBx, which has a size of ~17 kDa, can physically bind to AR . HBx-mediated enhancement of AR activity is androgen-dependent and could be mediated through indirect mechanism involving calcium and c-Src signaling pathways . HBx enhances the AR transcriptional activity through two kinases: c-Src and glycogen synthase kinase-3beta kinase . AR promotes HBV-induced hepatocarcinogenesis through modulation of HBV RNA transcription . The androgen pathway can increase the transcription of HBV through direct binding to the ARE sites in HBV enhancer I, leading to a higher HBV titer in male carriers and increased risk of HCC . These facts together suggest that the targeting of AR might be developed as a new therapeutic strategy against HBV-related HCC .
Ma et al.  reported that mice lacking hepatic AR developed later and less HCC than their wild-type littermates with comparable serum testosterone in both males and females when using the Cre-Lox conditional knockout mouse model injected with carcinogen and that AR may promote hepatocarcinogenesis via increased cellular oxidative stress and DNA damage, as well as by suppression of p53-mediated DNA damage sensing/repairing system and cell apoptosis. Recently, it has been shown that vertebrae forkhead box A (Foxa) factors and their targets estrogen receptor (ERα) and/or AR play an important role in the sexual dimorphism of HCC . In conclusion, AR as well as ERα  could be involved in human hepatocarcinogenesis. Targeting AR might be developed as new molecular-target therapy against not only HBV-related but also HCV-related HCC.
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