MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A
Metrics: PDF 3442 views | HTML 2951 views | ?
Katsuya Ohta1, Hiromitsu Hoshino1, Jinhua Wang1, Shigeshi Ono1, Yuuki Iida1, Keisuke Hata1, Sharon K. Huang1, Steven Colquhoun2 and Dave S. B. Hoon1
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
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
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.