miR 122 enhances sensitivity of hepatocellular carcinoma to oxaliplatin via inhibiting MDR1 by targeting Wnt/b catenin pathway.
BACKGROUND Hepatocellular carcinoma (HCC) is one of the primary causes of cancer related death and resistance to cytotoxic chemotherapy is the major cause of mortality in HCC patients. miR 122 is a liver specific miRNA and is found to be reduced in HCC, however, the function of miR 122 in HCC chemosensitivity remains elusive. METHODS We used qRT PCR to measure expressions of miR 122, b catenin and MDR1 in four HCC cell lines. And we assessed the effects of miR 122 or b catenin on cell viability and apoptosis upon oxaliplatin (OXA) treatment by MTT assay and flow cytometry. In addition, we validated the interactions of miR 122/b catenin and b catenin/MDR1 by dual luciferase reporter assay and chromatin immunoprecipitation (ChIP) Western blotting was used to determine the protein levels of b catenin, Wnt1 and MDR1. In the end, we verified the anti tumor effect of miR 122 in vivo by using mouse tumor xenograft model. RESULTS We found that miR 122 was down regulated in HCC cells. Up regulation of miR 122 or inhibition of Wnt/b catenin signaling promoted HCC cells apoptosis and increased the sensitivity of HCC cells to OXA. On the molecular level, we showed that miR 122 directly targeted and suppressed Wnt/b catenin pathway while b catenin bound with MDR1 promoter and activated its transcription. Overexpression of miR 122 inhibited MDR1 expression via directly suppressing Wnt/b catenin pathway. CONCLUSION Our study fully demonstrated that miR 122 inhibits MDR1 expression via suppression of Wnt/b catenin pathway, thereby enhancing HCC sensitivity to OXA. Therefore, miR 122 could serve as a novel potential therapeutic target for HCC.
Experimental and molecular pathology