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 D Colquhoun, Dave S.B. Hoon

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

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 tumorsuppressor 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.

Original languageEnglish (US)
Pages (from-to)3211-3224
Number of pages14
JournalOncotarget
Volume6
Issue number5
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • Drug-sensitivity
  • Hepatocellular carcinoma
  • miR-93
  • Sorafenib and tivantinib

ASJC Scopus subject areas

  • Oncology

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