title: miR-874-3p is down-regulated in hepatocellular carcinoma and negatively regulates PIN1 expression.
abstract: PIN1 is a peptidyl-prolyl cis/trans isomerase (PPIase) that regulates multiple signaling pathways to control cell fate and is found to be over-expressed in cancers, including hepatocellular carcinoma (HCC). However, the regulation of PIN1 in HCC remains poorly defined. Micro-RNAs (miRNAs) have been reported to play a pivotal role in oncogenesis by targeting the 3'-untranslated region (UTR) of mRNAs encoded by oncogenes and tumour suppressor genes, thereby suppressing the levels of both oncoproteins and tumour suppressors. In this report, we aimed to identify miRNAs that suppress PIN1 expression and to determine their role in HCC. By searching the TargetScan database, miR-874-3p was identified as a potential negative regulator of PIN1. miR-874-3p was demonstrated to bind the 3'UTR of PIN1 mRNA directly to suppress expression of PIN1. Functionally, over-expression of miR-874-3p in HCC cell line PLC/PRF/5 inhibited cell growth and colony formation in-vitro, and promoted cellular apoptosis. Furthermore, these tumour suppressive functions conferred by miR-874-3p were abrogated by over-expression of PIN1. Similarly, expression of miR-874-3p in PLC/PRF/5 with PIN1 knocked-down did not further suppress cellular proliferation, suggesting that PIN1 was a major target of miR-874-3p. More importantly, miR-874-3p was found to be down-regulated in HCC tissues and its expression was negatively correlated with that of PIN1. Down-regulation of miR-874-3p was also associated with poorly differentiated tumour cells, more advanced staging, and inferior patient outcomes. In addition, over-expression of miR-874-3p suppressed tumour growth in vivo. Taken together, our data suggested that miR-874-3p plays a tumour suppressive role in HCC through down-regulation of PIN1.
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Ka-Wai
authors.initials: KW
authors.lastname: Leong
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Chi-Wai
authors.initials: CW
authors.lastname: Cheng
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Yok-Lam
authors.initials: YL
authors.lastname: Kwong
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Eric
authors.initials: E
authors.lastname: Tse
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000096:biosynthesis* / Q000235:genetics; D016133:Polymerase Chain Reaction
chemical_list: C561946:MIRN874 microRNA, human; D035683:MicroRNAs; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human
keywords: PIN1; hepatocellular carcinoma; miR-874-3p; micro-RNA; peptidyl-prolyl-isomerase