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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Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated. By examining the expression of 22 HCC-related miRNAs between precancerous and cancerous liver tissues, we found miR-216a and miR-224 were significantly up-regulated, starting from the precancerous stage. Furthermore, the elevation of miR-216a was mainly identified in male patients. To study this gender difference, we demonstrated that pri-miR-216a is activated transcriptionally by the androgen pathway in a ligand-dependent manner and is further enhanced by the hepatitis B virus X protein. The transcription initiation site for pri-miR-216a was delineated, and one putative androgen-responsive element site was identified within its promoter region. Mutation of this site abolished the elevation of pri-miR-216a by the androgen pathway. One target of miR-216a was shown to be the tumor suppressor in lung cancer-1 gene (TSLC1) messenger RNA (mRNA) through the three target sites at its 3 0 untranslated region. Finally, the androgen receptor level increased in male liver tissues during hepatocarcinogenesis, starting from the precancerous stage, with a concomitant elevation of miR-216a but a decrease of TSLC1. Conclusion: The current study discovered the up-regulation of miRNA-216a by the androgen pathway and a subsequent suppression of TSLC1 as a new mechanism for the androgen pathway in early hepatocarcinogenesis. (HEPATOLOGY 2012;56:632-643) T he incidence of hepatocellular carcinoma (HCC) ranks fifth for cancers worldwide and causes about half a million deaths every year. 1 HCC is usually the ultimate outcome of chronic hepatitis caused by persistent viral infection (hepatitis B or C virus [HBV/HCV]) or by alcoholic/metabolic etiologies. After decades of chronic hepatitis, which might induce persistent necrosis and regeneration and accumulate the carcinogenic events in the hepatocytes, about 30%-40% of patients will progress into liver cirrhosis, and those will subsequently develop HCC with an annual incidence around 1%-5%. 2 Due to the multistep characteristic of cancer development, on average six to seven successive mutations are generally believed to be required to convert a normal hepatocyte into an invasive HCC. 3 As every mutation contributes to the formation of an expanded clone and thus presents a larger target population of cells for the next mutation, the cells surrounding the HCC could be considered precancerous cells, retaining the potential to become the subsequent HCC. 4 This