miR-483-3p and drug resistance in Hepatocarcinoma (VeromiRNA)
miR-483-3p and drug resistance in Hepatocarcinoma
Date du début: 1 oct. 2012,
Date de fin: 30 sept. 2016
Hsa-mir-483 is located within intron 2 of the INS-IGF2 gene. We have previously shown oncogenic features of miR-483-3p targeting the pro-apoptotic gene BBC3/PUMA (P53 up-regulated modulator of apoptosis gene) giving drug resistance to cells. Generally the IGF2 and miR-483 expression are strictly correlated although we have demonstrated that expression of miR-483 can be induced independently of IGF2 by the oncoprotein b-catenin. In Hepatocarcinoma (HCC) IGF2/483 locus is often over-expressed probably by Loss of Imprinting (LOI) at the IGF2/H19 imprinted control region (ICR) and HepG2 and Hep3B HCC cell lines shown the entire IGF2/483 locus up-regulated. As a matter of fact we found that the treatment with the de-methylating agent 5-azacytidine, induces an important down-regulation of IGF2 and miR-483-3p genes.Moreover, during the course of our study we found that the chemotherapeutic drug 5-fluoruracyl (5-FU) induces increased expression of miR-483-3p in HepG2 and Hep3B cells. 5-FU treatment does not affect all the HCC cell lines that we tested suggesting a possible heterogeneity in cellular drug resistance dependently from miR-483-3p induced expression. Aim of this project is to investigate the mechanism involved in the 5-FU/miR-483 regulation, identify its importance in chemotherapeutic resistance in HCC primary tissues and explore if a concomitant treatment with the de-methylating agent 5-azacytidine and chemotherapeutic 5-FU, could improve the susceptibility to apoptosis of cancer cells.
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