Table 1.

Functional activities of specific miRNAs in HBV-associated hepatocarcinogenesis process between female and male.

miRNA-145	In HBV-related HCC patients the global miRNA expression profiles are different from those of nontumorous liver tissues. Among examined miRNAs, miRNA-145 is frequently downregulated in HBV-associated HCC patients. Its overexpression can inhibit cell proliferation and invasion of HCC cells. Therefore, it has been suggested that miRNA-145 can act as a negative regulator of proliferation and invasion of HCC cells. In addition, it also regulates some properties of cancer stem cells (CSCs) such as stem cell differentiation and stem cell self-renewal by negatively modulating the expression of protooncogene c-myc and pluripotency factors SOX-2, OCT4, and KLF4. These data suggest that miRNA-145 can be a tumor suppressor miRNA and may play a crucial role in HCC development
miRNA-216a	Various studies showed that there is a gender disparity in the pattern of expression of miRNA-216a in precancerous liver tissues. In female no upregulation of miRNA-216a expression was observed. Conversely, in premalignant liver tissues of male HBV-related HCC patients, the androgen signal can activate and increase miRNA-216a transcription by directly binding to the site ARE within the promoter region of pri-miRNA-216a. This leads to an increase of the miRNA-216a level and subsequent suppression of its target genes (e.g., TSCL1) through an important self-amplifying positive loop including AR, CCRK, and β-catenin/T cell factor (TCF) signaling in HCC cell lines and animal models. Notably, miRNA-216a levels can also be used as excellent prognostic biomarkers. In addition, ligand-activated AR can also stimulate the HBV RNA transcription by binding to ARE sites in enhancer I of the HBV genome. This leads to replication of HBV genes and HBX expression which in turn activates c-Src kinase and inactivates GSK-3 contributing to full activation of AR. These results indicate that there is an interesting positive cross-regulatory loop between the androgen signal and the HBX viral protein that can significantly contribute to male HBV-related HCC development
miRNA-22	In some female patients, the estrogen signal exerts oncosuppressive activity by suppressing IL-1α transcription by binding to the human IL-1α promoter. In addition, in female miRNA-22 expression is not significantly increased. Conversely, in male the androgen signal exerts oncogenic activity by increasing miRNA-22 expression in tumor adjacent tissue compared with controls. Increased expression of miRNA-22 in male tumor adjacent tissue might inhibit ER-α expression by directly targeting the 3′-UTR region of ER mRNA. This leads to attenuation of the protective effect of estrogen, causing increased IL-1α expression. Finally, this persistent overexpression of IL-1α from necrotic hepatocytes might lead to a compensatory proliferative response and tumorigenesis in normal hepatic cells.
miRNA-18a	In female, increased expression of miRNA-18a due to elevated/mutant p53 reduces ER-α levels by binding to its mRNA at the 3′-untranslated region (3′-UTR). It seems that elevated/mutant p53 plays a key role in modulating the amount of ER-α protein by promoting the biogenesis of miRNA-18a. By this mechanism, miRNA-18a could suppress the estrogen signal and promote the development of HCC in women.