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 journalArticle

101 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

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Keywords

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

ASJC Scopus subject areas

  • Oncology

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