title: Estradiol induces apoptosis via activation of miRNA-23a and p53: implication for gender difference in liver cancer development.
abstract: Estrogen (E2) has been suggested to have a protective role in attenuating hepatocellular carcinoma (HCC) development. miRNAs have great potential as biomarkers and therapeutic agents owing to their ability to control gene expression. However, little is known about the mechanism underlying the protective role of E2 in hepatocarcinogenesis and the effects of E2 on apoptotic miRNAs expression. Using miRNA PCR array, we found more than 2-fold alteration was observed in 25 upregulated and 10 downregulated apoptotic miRNAs in E2-treated cells. Among these miRNAs, we found expression of miR-23a was related to p53 functional status in the male-derived liver cell-lines. We demonstrated that E2 via ERα transcriptionally activated miR-23a and p53 expression, and thus enhanced p53 activation of miR-23a expression. Moreover, miR-23a expression correlated inversely with the expression of target gene X-linked inhibitor of apoptosis protein (XIAP), but positively with the caspase-3/7 activity. Decreasing of XIAP might contribute to caspase-3 activity and cell apoptosis. Taken together, our findings reveal a novel E2-signaling mechanism in regulating miRNAs expression for controlling apoptosis in liver cells. Delineating the role of E2 in regulating the activation of p53 and miR-23a, expression in HCC is crucial to the understanding of the sex difference observed in HCC.
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR.
authors.forename: Fung-Yu
authors.initials: FY
authors.lastname: Huang
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR.
authors.forename: Danny Ka-Ho
authors.initials: DK
authors.lastname: Wong
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR.
authors.forename: Wai-Kay
authors.initials: WK
authors.lastname: Seto
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR.
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Lai
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR.
authors.forename: Man-Fung
authors.initials: MF
authors.lastname: Yuen
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D012727:Sex Characteristics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
chemical_list: C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D004958:Estradiol
keywords: apoptosis; estrogen; gender difference; hepatocellular carcinoma; microRNA