MicroRNA-122 Inhibits Tumorigenic Properties of Hepatocellular Carcinoma Cells and Sensitizes These Cells to Sorafenib

• Published in: The Journal of biological chemistry Vol. 284; no. 46; pp. 32015 - 32027
• Main Authors: Bai, Shoumei, Nasser, Mohd W., Wang, Bo, Hsu, Shu-Hao, Datta, Jharna, Kutay, Huban, Yadav, Arti, Nuovo, Gerard, Kumar, Pawan, Ghoshal, Kalpana
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.11.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Antineoplastic Agents - pharmacology; Benzenesulfonates - pharmacology; Blotting, Western; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Proliferation - drug effects; Humans; In Situ Hybridization; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Luciferases - metabolism; Mice; Mice, Nude; MicroRNAs - physiology; Niacinamide - analogs & derivatives; Phenylurea Compounds; Pyridines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Mediated Regulation and Noncoding RNAs; Sorafenib; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.016774

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 (adistintegrin 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.