The DNA Methylation Regulated MicroRNAs Perspective Of The Mechanistic Insights In Cancer Chemosensitivity: The 5-FU/Hepatocellular Carcinoma Paradigm

Chemoresistance is one of the major hurdles in optimal cancer chemotherapy and hard to be defined in advance. Both confirmation of clinical relevance and elucidation of mechanistic details of the molecular defects that have been revealed from the genomic study are required for the robust cancer diagnostics (prognostics) and therapeutics.Hepatocellular carcinoma (HCC) represents one of the most aggressive malignancies, pronounced for its refractoriness to chemotherapy. Started from the genomic studies at both DNA methylation and microRNAs levels, we found that the chemoresistance of HCC to 5-florouracil (5-FU) is mediated by DNA methylation regulated miR-193a-3p gene, which expresses low and is hypermethylated in QGY-7703 (5-FU IC50=0.39ug/ml) but expresses high and hypomethylated in SMMC-7721(5-FU IC5o=41.01ug/ml). Forced elevation of miR-193a-3p in the mimic transfected QGY-7703 and repression in the antagomir transfected SMMC-7721 turned around 5-FU sensitivity in cell culture as well as both 5-FU sensitivity and tumorigeneity in nude mice. The siRN A mediated repression of a miR-193a-3p target, SFRS2 (a key mRNA splicing factor) expression reproduced all the phenotypic changes in the mimic transfected QGY-7703 cells. Our findings provides a novel mechanism underlying tumor aggression and 5-FU sensitivity of HCC, which involves the DNA methylation's control of miR-193a expression, miR-193a-3p's repression of SFRS2 expression and SFRS2 regulated expression of the proapoptotic versus antiapoptotic splicing forms of caspase 2, the molecular events of which are the targets for the future development and use of the assay for rationale 5-FU therapy of HCC. Indeed, the preliminary data in the clinical setting indicate the predictictive value of the SFRS2 expression for both survival and outcome of the 5-FU chemotherapy of HCC patients.