title: MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib.
abstract: MicroRNAs are negative regulators of protein coding genes. The liver-specific microRNA-122 (miR-122) is frequently suppressed in primary hepatocellular carcinomas (HCCs). In situ hybridization demonstrated that miR-122 is abundantly expressed in hepatocytes but barely detectable in primary human HCCs. Ectopic expression of miR-122 in nonexpressing HepG2, Hep3B, and SK-Hep-1 cells reversed their tumorigenic properties such as growth, replication potential, clonogenic survival, anchorage-independent growth, migration, invasion, and tumor formation in nude mice. Further, miR-122-expressing HCC cells retained an epithelial phenotype that correlated with reduced Vimentin expression. ADAM10 (a distintegrin and metalloprotease family 10), serum response factor (SRF), and insulin-like growth factor 1 receptor (Igf1R) that promote tumorigenesis were validated as targets of miR-122 and were repressed by the microRNA. Conversely, depletion of the endogenous miR-122 in Huh-7 cells facilitated their tumorigenic properties with concomitant up-regulation of these targets. Expression of SRF or Igf1R partially reversed tumor suppressor function of miR-122. Further, miR-122 impeded angiogenic properties of endothelial cells in vitro. Notably, ADAM10, SRF, and Igf1R were up-regulated in primary human HCCs compared with the matching liver tissue. Co-labeling studies demonstrated exclusive localization of miR-122 in the benign livers, whereas SRF predominantly expressed in HCC. More importantly, growth and clonogenic survival of miR-122-expressing HCC cells were significantly reduced upon treatment with sorafenib, a multi-kinase inhibitor clinically effective against HCC. Collectively, these results suggest that the loss of multifunctional miR-122 contributes to the malignant phenotype of HCC cells, and miR-122 mimetic alone or in combination with anticancer drugs can be a promising therapeutic regimen against liver cancer.
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Shoumei
authors.initials: S
authors.lastname: Bai
authors.forename: Mohd W
authors.initials: MW
authors.lastname: Nasser
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Shu-Hao
authors.initials: SH
authors.lastname: Hsu
authors.forename: Jharna
authors.initials: J
authors.lastname: Datta
authors.forename: Huban
authors.initials: H
authors.lastname: Kutay
authors.forename: Arti
authors.initials: A
authors.lastname: Yadav
authors.forename: Gerard
authors.initials: G
authors.lastname: Nuovo
authors.forename: Pawan
authors.initials: P
authors.lastname: Kumar
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ghoshal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D010671:Phenylurea Compounds; D011725:Pyridines; D012333:RNA, Messenger; D009536:Niacinamide; D000077157:Sorafenib; D008156:Luciferases