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Mir-424 and Mir-503 Regulates Cobll1 Expression during the CML Progression

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Up- or down-regulation of many miRNAs plays an important role in chronic myeloid leukemia (CML), however underlying mechanisms remain to be elucidated. Here, we report miRNA-424 and miR-503 regulates Cobll1… Click to show full abstract

Up- or down-regulation of many miRNAs plays an important role in chronic myeloid leukemia (CML), however underlying mechanisms remain to be elucidated. Here, we report miRNA-424 and miR-503 regulates Cobll1 expression during CML progression. In previous our study, Cobll1 is a novel oncoprotein to associate with drug resistance and CML progression and highly expressed in blast crisis (BC). Also, overexpression of Cobll1 for blast formation and independently of BCR-ABL1 could be achieved in several ways. It could be by altering unknown signaling pathway(s), and being independent from BCR-ABL1. We searched for miRNAs that can regulate the expression level of Cobll1 to examine potential regulators of Cobll1 . To find candidate miRNAs of Cobll1 , we were predicted to miRNA (miR-15a, miR-16, miR-103, miR-107, miR-424 and miR-503) by the algorithm in the TargetScan software. To validation target miRNA of Cobll1 , we analyzed the expression levels of these miRNAs in CP and BC samples of 2 CML patients. Interestingly, miR-424 and miR-503 expression were significantly reduced in BC, which indicates that expression of Cobll1 and miR-424 or miR-503 is negative correlation. We next performed that eighty one CML samples (41 CP and 40 BC) were analyzed to determine the levels of the Cobll1 protein/miR-424 and miR-503 by Western blotting/qRT-PCR. Amazingly, we found that miR-424 and miR-503 were significantly downregulated highly expressed Cobll1 BC samples (n=21) compared to Cobll1 less expressed BC samples (n=19) and CP samples (n=41). Interestingly, there were down-regulations in expression of miR-424 and miR-503 that had high co-relation with Cobll1 expression in CML progression. To assess the effects of miR-424 or miR-503 regulates Cobll1 expression, we make ectopically expressing plasmids of wild-type Cobll1 39-UTR and mutant Cobll1 39-UTR. Transfection of miR-424 or miR-503 reduced luciferase activity in K562 cells ectopically expressing wild-type Cobll1 39-UTR, but not a mutant Cobll1 39-UTR. In addition, overexpression of miR-424 or miR-503 significantly reduced the endogenous Cobll1 levels in K562 cells. Consistently, the knockdown of Cobll1 by the miRNAs sensitized K562 cells to nilotinib-induced apoptosis. Taken together, our findings suggest that miR-424 and miR-503 plays a critical role CML by targeting directly targeting the Cobll1. These results provide the clue of miR-424 and miR-503 as a potential therapeutic target for CML progression by regulating the Cobll1 expression. Disclosures No relevant conflicts of interest to declare.

Keywords: mir 424; mir 503; mir; cobll1; expression; 424 mir

Journal Title: Blood
Year Published: 2017

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