Increased Ras GTPase activity is regulated by miRNAs that can be attenuated by CDF treatment in pancreatic cancer cells

Ras gene is frequently mutated, and also associated with increased Ras expression and its GTPase activity (activity) in pancreatic cancer (PC), which could in part be due to deregulated expression of microRNAs (miRNAs) contributing to tumor aggressiveness. Here we report, for the first time, that Ras expression and its activity were significantly higher in MIAPaCa-2 cells compared to COLO-357 and BxPC-3 cell lines, which was correlated with loss of let-7 family and miR-143 expression in MIAPaCa-2 cells compared to COLO-357 and BxPC-3 cells. Whereas the expression of miR-21, a frequently up-regulated miRNA in solid tumors was up-regulated in MIAPaCa-2 cells and it was correlated with increased Ras expression and its activity. The miRNAs, let-7i and miR-143 was found to target Ras, and forced re-expression of let-7i and miR-143 inhibited Ras activity, cell proliferation and colony formation in vitro. We also found that the treatment of cells in vitro or treatment of MIAPaCa-2 induced tumors in vivo with CDF, a novel synthetic analog of curcumin, led to the re-expression of let-7 and miR-143, and down-regulated miR-21 expression, which was consistent with attenuation of Ras expression and its activity. Moreover, re-expression of let-7iin vivo resulted in decreased tumor growth and Ras activity. These results suggest that the loss of expression of let-7 and miR-143, and increased expression of miR-21 leads to increased expression of Ras and its GTPase activity, which could be attenuated by CDF treatment and, thus CDF could become a novel therapeutic agent for the treatment of PC.