MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A

• Published in: Oncotarget Vol. 6; no. 5; pp. 3211 - 3224
• Main Authors: Ohta, Katsuya, Hoshino, Hiromitsu, Wang, Jinhua, Ono, Shigeshi, Iida, Yuuki, Hata, Keisuke, Huang, Sharon K, Colquhoun, Steven, Hoon, Dave S B
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20.02.2015
• Subjects: 3' Untranslated Regions; Adult; Aged; Aged, 80 and over; Apoptosis; Binding Sites; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Movement; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Hep G2 Cells; Humans; Liver Neoplasms - enzymology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Phenylurea Compounds - pharmacology; Phosphatidylinositol 3-Kinase - metabolism; Prognosis; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Pyrrolidinones - pharmacology; Quinolines - pharmacology; Research Paper; Sorafenib; Time Factors; Transfection; Up-Regulation
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3085

To assess the role of microRNAs (miR) in hepatocellular carcinoma (HCC), we performed comprehensive microRNA expression profiling using HCC cell lines and identified miR-93 as a novel target associated with HCC. We further verified miR-93 expression levels in advanced HCC tumors (n=47) by a direct PCR assay and found that elevated miR-93 expression level is significantly correlated with poor prognosis. Elevated miR-93 expression significantly stimulated in vitro cell proliferation, migration and invasion, and additionally inhibited apoptosis. We confirmed that miR-93 directly bound with the 3' untranslated regions of the tumor-suppressor genes PTEN and CDKN1A, respectively,and inhibited their expression. As a result of this inhibition, the c-Met/PI3K/Akt pathway activity was enhanced. IHC analysis of HCC tumors showed significant correlation between c-Met protein expression levels and miR-93 expression levels. Knockdown of c-Met inhibited the activation of the c-Met/PI3K/Akt pathway regardless of hepatocyte growth factor (HGF) treatment, and furthermore reduced the expression of miR-93 in these HCC cells. miR-93 also rendered cells to be more sensitive to sorafenib and tivantinib treatment. We concluded that miR-93 stimulated cell proliferation, migration, and invasion through the oncogenic c-Met/PI3K/Akt pathway and also inhibited apoptosis by directly inhibiting PTEN and CDKN1A expression in human HCC.