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

2014; Impact Journals LLC; Volume: 6; Issue: 5 Linguagem: Inglês

10.18632/oncotarget.3085

1949-2553

Katsuya Ohta, Hiromitsu Hoshino, Jinhua Wang, Shigeshi Ono, Yuuki Iida, Keisuke Hata, Sharon K. Huang, Steven D. Colquhoun, Dave S.�B. Hoon,

Cancer Mechanisms and Therapy

// Katsuya Ohta 1 , Hiromitsu Hoshino 1 , Jinhua Wang 1 , Shigeshi Ono 1 , Yuuki Iida 1 , Keisuke Hata 1 , Sharon K. Huang 1 , Steven Colquhoun 2 and Dave S. B. Hoon 1 1 Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA 2 Liver Disease and Transplant Center, Cedars-Sinai Medical Center, Beverly Hills, CA, USA Correspondence: Dave S. B. Hoon, email: // Keywords : miR-93, hepatocellular carcinoma, drug-sensitivity, sorafenib and tivantinib Received : September 09, 2014 Accepted : December 23, 2014 Published : December 26, 2014 Abstract 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.