Background: Activation of IGF-1/IGF-1R signaling cascade is a hallmark in Hepatocellular carcinoma (HCC). In our previous work, we showed that miR-486-5p acts as a tumor suppressor miRNA in HCC mainly by vertically blocking IGF-1/IGF-1R axis and its downstream signaling mediators STAT3, mTOR and c-Myc. Recently, it was reported that the proto-oncogene c-Myc directly down-regulates the tumor suppressor miRNA, let-7a, especially in HCC and that let-7 directly targets the oncogenic RNA binding protein IGF2BP1. Aim: Therefore, the main aim of this study was to investigate the indirect interplay between microRNAs; miR-486-5p and miR-let- 7a through c-MYC thereby its effect on a vital member of IGF-axis, IGF2BP1, in HCC. Methods: Huh-7 cell lines were cultured and transfected using miR-486-5p mimics using lipofection technique. Forty-eight hours post transfection, total RNA was extracted, reverse transcribed into cDNA, and finally amplified and quantified using q-RT-PCR. Impact of miR-486-5p on cell cycle was assessed using cell cycle vectors carrying response elements for the cell cycle protein c-Myc. Results: Efficient delivery of miR-486-5p in Huh-7 cells was obtained, where mimicked cells showed more than 8000 folds increase in miR-486-5p expression level. Ectopic expression of miR- 486-5p in Huh-7 cells resulted in a significant decrease in c-Myc protein expression, an increase in the expression level of the tumor suppressor, let-7a and finally forcing the expression of miR-486-5p showed a significant repression of the oncogenic validated target of let-7a, IGF2BP1. Conclusions: This study shows a novel mechanism of action of the tumor suppressor miR-486-5p. MiR-486-5p was found to indirectly repress an essential member of IGF-axis, the oncogenic RNA binding protein IGF2BP1, mainly through decreasing c-MYC expression and up regulating let-7a expression.
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[v1] 2017-08-23 06:21:38
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