title: Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma.
abstract: Gemcitabine (GEM), a commonly used chemotherapeutic agent in hepatocellular carcinoma (HCC) patients, uses oxidative stress induction as a common effector pathway. However, GEM alone or in combination with oxaliplatin hardly renders any survival benefits to HCC patients. We have recently shown that this is part due to the overexpression of the mitochondrial uncoupling protein 2 (UCP2) that in turn mediates resistance to GEM in HCC patients. However, not much is known about regulatory mechanisms underlying UCP2 overexpression in HCC. Differential protein expression in HCC cell lines did not show a concomitant change in UCP2 transcript level, indicating post-transcriptional or post-translational regulatory mechanism. In situ analysis revealed that UCP2 is a putative target of miR-214 miR-214 expression is significantly down-regulated in HCC patient samples as compared with normal adjacent tissues and in cell line, human hepatoblastoma cells (HuH6), with high UCP2 protein expression. We demonstrated using miR-214 mimic and antagomir that the miRNA targeted UCP2 expression by directly targeting the wild-type, but not a miR-214 seed mutant, 3' UTR of UCP2 Overexpression of miR-214 significantly attenuated cell proliferation. Finally, analysis in 20 HCC patients revealed an inverse correlation in expression of UCP2 and miR-214 (Pearson's correlation coefficient, r=-0.9792). Cumulatively, our data indicate that in the context of HCC, miR-214 acts as a putative tumour suppressor by targeting UCP2 and defines a novel mechanism of regulation of UCP2.
authors.affiliation: Department of Hepatobiliary Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, China Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, China.
authors.forename: Guangsheng
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Hepatobiliary Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, China.
authors.forename: Jianlu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, China jiahongdong1@163.com kesenxu@163.com.
authors.forename: Kesen
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, China Department of Hepatobiliary Surgery, Chinese General PLA Hospital, Beijing 100853, China jiahongdong1@163.com kesenxu@163.com.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Dong
mesh_terms: D020413:3' Untranslated Regions; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D000071246:Uncoupling Protein 2 / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2
keywords: HepG2; cell; hepatocellular carcinoma (HCC); uncoupling protein 2 (UCP2); uncoupling proteins