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 language | English (US) |
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Pages (from-to) | 3211-3224 |
Number of pages | 14 |
Journal | Oncotarget |
Volume | 6 |
Issue number | 5 |
DOIs | |
State | Published - 2015 |
Externally published | Yes |
Keywords
- Drug-sensitivity
- Hepatocellular carcinoma
- miR-93
- Sorafenib and tivantinib
ASJC Scopus subject areas
- Oncology