The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma

Satoshi Shimizu, Tetsuo Takehara, Hayato Hikita, Takahiro Kodama, Takuya Miyagi, Atsushi Hosui, Tomohide Tatsumi, Hisashi Ishida, Takehiro Noda, Hiroaki Nagano, Yuichiro Doki, Masaki Mori, Norio Hayashi
Journal of Hepatology 2010, 52 (5): 698-704

BACKGROUND & AIMS: Bcl-xL, an anti-apoptotic member of the Bcl-2 family, is over-expressed in human hepatocellular carcinoma, conferring a survival advantage to tumour cells. The mechanisms underlying its dysregulation have not been clarified. In the present study, we explored the involvement of microRNAs that act as endogenous sequence-specific suppressors of gene expression.

METHODS: The expression profiles of microRNAs in Huh7 hepatoma cells and primary human hepatocytes were compared by microarray analysis. The effect of let-7 on Bcl-xL expression was examined by Western blot and a reporter assay. The involvement of let-7 microRNAs in human tissues was analysed by western blot and reverse transcription-PCR.

RESULTS: Microarray analysis, followed by in silico target prediction, identified let-7 microRNAs as being downregulated in Huh7 hepatoma cells in comparison with primary human hepatocytes, as well as possessing a putative target site in the bcl-xl mRNA. Over-expression of let-7c or let-7g led to a clear decrease of Bcl-xL expression in Huh7 and HepG2 cell lines. Reporter assays revealed direct post-transcriptional regulation involving let-7c or let-7g and the 3'-untranslated region of bcl-xl mRNA. Human hepatocellular carcinoma tissues with low expression of let-7c displayed higher expression of Bcl-xL protein than those with high expression of let-7c, suggesting that low let-7 microRNA expression contributes to Bcl-xL over-expression. Finally, expression of let-7c enhanced apoptosis of hepatoma cells upon exposure to sorafenib, which downregulates expression of another anti-apoptotic Bcl-2 protein, Mcl-1.

CONCLUSIONS: let-7 microRNAs negatively regulate Bcl-xL expression in human hepatocellular carcinomas and induce apoptosis in cooperation with an anti-cancer drug targeting Mcl-1.

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