The Function And Mechanism Of MiR-21 In Modulating 5-Fu Resistance Of Pancreatic Cancer Cells

Background and objective: The drug-resistant nature of pancreatic cancer cells results in poor therapeutic effect. To predict the therapeutic effect of the chemotherapy drugs to specific patient and to reverse the resistance of pancreatic cancer cells are critical for chemotherapy of pancreatic cancer.microRNAs have been reported to play important roles in the genesis of drug-resistance of various cancer types. There are also many advantages of microRNAs in diagnosis and therapy of disease. However, there is few reports about microRNAs in regulating drug-resistant nature of pancreatic cancer cells. We identified many miRNAs which and found that miR-21 was significantly up-regulated in the 5-Fu resistant cells. The overexpression of miR-21 in pancreatic cancer cells strongly promoted cell survival when treated with 5-Fu and also advanced cell proliferation and invasion. The primary investigation of miR-21 expression in pancreatic specimens suggested that high expression of miR-21 was correlated with worse outcome in PDAC patients treated with 5-Fu.Objective: We mainly study the function and mechanism of miR-21 modulating drug resistance of pancreatic cancer cells.Methods: The drug sensitivity was assessed by calculating IC50 values. The expression of microRNA-21 was determined by real-time PCR. Recombinant lentivirus was used to enhance the expression level of microRNA-21. The migration and invasion capacity of pancreatic cancer cells was investigated by wound healing and transwell assay. Moreover, the expression of proteins involved in the regulation of drug sensitivity was evaluated by Western blot.Results: We reported that miR-21 increased significantly in 5-FU resistant PATU8988 cells compared with the primary sensitive PATU8988 cells. Lentivirus-mediated overexpression of miR-21 not only conferred resistance to 5-FU, but also promoted proliferation, migration and invasion of PATU8988 and PANC-1 cells. Furthermore, the promoting effects of miR-21 on drug resistance were attributed to the attenuated expression of its tumor suppressor targets PTEN and Programmed cell death 4(PDCD4). Enforced expression of PTEN and PDCD4 can antagonize miR-21-induced resistance to 5-FU and stimulative migration activity.Conclusions: 1. miR-21 can confer drug resistance to 5-FU in pancreatic cancer cells, by regulating the expression of tumor suppressor genes.2. As the target genes of miR-21, PTEN and PDCD4 can rescue 5-FU sensitivity and phenotypic characteristics disrupted by miR-21.