title: Gα12 gep oncogene deregulation of p53-responsive microRNAs promotes epithelial-mesenchymal transition of hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) has a poor prognosis owing to aggressive phenotype. Gα12 gep oncogene product couples to G-protein-coupled receptors, whose ligand levels are frequently increased in tumor microenvironments. Here, we report Gα12 overexpression in human HCC and the resultant induction of zinc-finger E-box-binding homeobox 1 (ZEB1) as mediated by microRNA deregulation. Gα12 expression was higher in HCC than surrounding non-tumorous tissue. Transfection of Huh7 cell with an activated mutant of Gα12 (Gα12QL) deregulated microRNA (miRNA or miR)-200b/a/429, -194-2/192 and -194-1/215 clusters in the miRNome. cDNA microarray analyses disclosed the targets affected by Gα12 gene knockout. An integrative network of miRNAs and mRNA changes enabled us to predict ZEB1 as a key molecule governed by Gα12. Decreases of miR-200a/b, -192 and -215 by Gα12 caused ZEB1 induction. The ability of Gα12 to decrease p53 levels, as a result of activating protein-1 (AP-1)/c-Jun-mediated mouse double minute 2 homolog induction, contributed to transcriptional deregulation of the miRNAs. Gα12QL induced ZEB1 and other epithelial-mesenchymal transition markers with fibroblastoid phenotype change. Consistently, transfection with miR-200b, -192 or -215 mimic prevented the ability of Gα12QL to increase tumor cell migration/invasion. In xenograft studies, sustained knockdown of Gα12 decreased the overall growth rate and average volume of tumors derived from SK-Hep1 cell (mesenchymal-typed). In HCC patients, miR-192, -215 and/or -200a were deregulated with microvascular invasion or growth advantage. In the HCC samples with higher Gα12 level, a correlation existed in the comparison of relative changes of Gα12 and ZEB1. In conclusion, Gα12 overexpressed in HCC causes ZEB1 induction by deregulating p53-responsive miRNAs, which may facilitate epithelial-mesenchymal transition and growth of liver tumor. These findings highlight the significance of Gα12 upregulation in liver tumor progression, implicating Gα12 as an attractive therapeutic target.
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors: Y M
authors: YM
authors: Yang
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors: W H
authors: WH
authors: Lee
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors: C G
authors: CG
authors: Lee
authors: Department of Internal Medicine, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors: J
authors: J
authors: An
authors: College of Pharmacy, Duksung Women's University, Seoul, South Korea.
authors: E-S
authors: ES
authors: Kim
authors: College of Medicine, Hanyang University, Seoul, South Korea.
authors: S H
authors: SH
authors: Kim
authors: Center for Liver Cancer, National Cancer Center, Goyang, South Korea.
authors: S-K
authors: SK
authors: Lee
authors: College of Medicine, Hanyang University, Seoul, South Korea.
authors: C H
authors: CH
authors: Lee
authors: Department of Cell Biology, OU Cancer Institute, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors: D N
authors: DN
authors: Dhanasekaran
authors: College of Pharmacy, Duksung Women's University, Seoul, South Korea.
authors: A
authors: A
authors: Moon
authors: College of Medicine, Hanyang University, Seoul, South Korea.
authors: S
authors: S
authors: Hwang
authors: College of Pharmacy, Gachon University, Incheon, South Korea.
authors: S J
authors: SJ
authors: Lee
authors: Center for Liver Cancer, National Cancer Center, Goyang, South Korea.
authors: J-W
authors: JW
authors: Park
authors: Department of Internal Medicine, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors: K M
authors: KM
authors: Kim
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors: S G
authors: SG
authors: Kim
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002642:Chick Embryo; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D044365:GTP-Binding Protein alpha Subunits, G12-G13