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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

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The estrogen pathway has long been implicated as a tumor protector in female hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Our previous study identified that estrogen receptor alpha (ERa) protein is downregulated in 60% of female HCC cases, via a miR-18a elevation mediated suppression of ERa translation. This study aims to delineate the mechanism underlying the upregulation of miR-18a in female HCC. The analysis of 77 female HCC specimens revealed that miR-18a levels were associated with pre-miR-18a rather than pri-miR-18a levels, suggesting an enhanced processing of pri-to pre-miR-18a. Among a panel of factors involved in microRNA processing, p53 was identified as a novel regulator for miR-18a maturation process. Knockdown of p53 by si-RNA decreased the level of miR-18a, whereas overexpression of either wild-type or mutant p53 increased its level. The association between the elevation of miR-18a and the accumulation of p53, mainly caused by somatic mutations, was confirmed in the clinical specimens of HBV-related female HCC. By analyzing the association with clinicopathological features, activation of this p53/miR-18a pathway mainly occurs in younger or noncirrhosis female HCC patients and associated with a trend of worse overall survival. Therefore, this study demonstrated a novel function of elevated/mutant p53 in regulating the amount of ERa protein through its promoting the biogenesis of miR-18a, which could lead to decrease the tumor-protective function of the estrogen pathway in female hepatocarcinogenesis.Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and its strong association with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is well known.1 Among the nonviral risk factors, the male sex factor has long been considered as a major risk factor of HCC, 2,3 as the incidence of HCC in male patients is 2-to 11-fold higher than that observed in females; this is even more evident in HBV-related HCC. 4 The sex hormones, including both the androgen and estrogen axes, are involved in the regulation of this gender difference in HCC. 4,5 The serial cohort studies performed by Yu et al. showed that an elevation in the activity of the androgen pathway was associated with higher HCC risk in male HBV carriers, whereas an elevation in the activity of the estrogen pathway was associated with lower HCC risk in female HBV carriers. 6 These results suggested opposite roles of the androgen and estrogen pathways in hepatocarcinogenesis, which might contribute to the gender difference of HCC.At the molecular level, recent studies have identified several mechanisms underlying the function of androgen and estrogen in the hepatocarcinogenic process. Regarding the androgen pathway, we found a positive regulatory loop between the viral Hepatitis B virus X protein and ligandactivated androgen receptor (AR) transcriptional activation in HBV-infected hepatocytes. This loop leads to persistently elevated AR activity and increased HBV mRNA transcription, which contribute to the ...

Genetic tractability and easy manipulation make Caenorhabditis elegans a good model to study host-pathogen interactions. Dozens of different bacterial species can pathogenically infect C. elegans under laboratory conditions, and all of these microbes are extracellular pathogens to nematodes. Viruses, on the other hand, are obligate intracellular parasites, and yet no viral infections have been reported for C. elegans. We established a procedure allowing vaccinia virus to enter and subsequently replicate in C. elegans. Virus replication was significantly enhanced in ced-3, ced-4, ced-9(gf), and egl-1(lf) mutants, demonstrating that the core programmed cell death (PCD) genes ced-3, ced-4, ced-9, and egl-1 control vaccinia virus replication in C. elegans. The ability of ced-3 and ced-4 alleles to restrict virus replication is correlated with their cell-killing activities. Moreover, the increase in vaccinia virus replication levels in the PCD-defective mutants was not likely to be caused by the extra live cells, as neither the inhibition of PCD by icd-1 overexpression nor the presence of extra cells after extra cell divisions in cul-1 or lin-23 mutants had any significant effect on vaccinia virus replication. Therefore, the core PCD genes possess a unique function in controlling vaccinia virus replication in C. elegans.programmed cell death ͉ virus-host interaction