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

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

doi:10.18632/oncotarget.3085

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

Oncotarget. 2015 Feb 20;6(5):3211-24. doi: 10.18632/oncotarget.3085.

Authors

Katsuya Ohta¹, Hiromitsu Hoshino¹, Jinhua Wang¹, Shigeshi Ono¹, Yuuki Iida¹, Keisuke Hata¹, Sharon K Huang¹, Steven Colquhoun², Dave S B Hoon¹

Affiliations

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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism*
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*
Pyrrolidinones / pharmacology
Quinolines / pharmacology
Sorafenib
Time Factors
Transfection
Up-Regulation

Substances

3' Untranslated Regions
ARQ 197
CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
MIRN93 microRNA, human
MicroRNAs
Phenylurea Compounds
Protein Kinase Inhibitors
Pyrrolidinones
Quinolines
Niacinamide
Sorafenib
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-met
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
PTEN protein, human