Abstract
Ribonucleotide reductase subunit M2 (RRM2) acts as an important gemcitabine resistance-related gene in pancreatic cancer (PC). Here, we aimed to investigate the potential microRNA that regulates gemcitabine chemosensitivity by targeting RRM2 and explores the clinical significance of candidate miRNA in PC. MTT assay and Western blot analysis revealed that long-time gemcitabine treatment in PC cells induced drug resistance and RRM2 increase, and silence of RRM2 blocked gemcitabine resistance. Among the predicted eight RRM2-related microRNAs, the expression of miR-20a-5p showed the most significant discrepancy between gemcitabine-resistant cells and parental cells. Furthermore, the Dual-Luciferase reporter gene assay indicated that miR-20a-5p directly targeted RRM2 3′UTR, thus inhibited expression of RRM2 and overcame gemcitabine resistance of PC cells. Retrospective study suggested that plasma miR-20a-5p level was correlated with gemcitabine resistance in PC patient. ROC curve showed that miR-20a-5p abundant level might predict gemcitabine resistance with an AUC of 89% (P<0.0001). Additionally, the PFS of patients with high and low expression levels miR-20a-5p was 2.8 and 4.5 months (P<0.001), respectively. Taken together, our results suggests that miR-20a-5p regulated gemcitabine chemosensitivity by targeting RRM2 in PC cells and could serve as a predictor for predicting the efficacy of gemcitabine-based chemotherapy in first-line treatment of PC patients.
Highlights
Pancreatic cancer (PC) has the highest mortality rate of all major cancers, with an overall survival rate of only approximately 5%
Evidence suggest that Ribonucleotide reductase (RR) plays a positive role in tumor cell proliferation and metastasis as well as the development of resistance to nucleoside analogs used in PC chemotherapy, including gemcitabine [4]
Previous evidence suggest that Ribonucleotide reductase subunit M2 (RRM2) could predict the prognosis of patients treated with gemcitabine, as relatively high expression of this gene in pancreatic cancer is associated with a poor prognosis, and patients who do not benefit from gemcitabine treatment tend to have elevated RRM2 expression [20]
Summary
Pancreatic cancer (PC) has the highest mortality rate of all major cancers, with an overall survival rate of only approximately 5%. Resistance to gemcitabine is a major obstacle to effective chemotherapy for PC. Ribonucleotide reductase (RR) is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides, the critical process of cell replication [2]. It is overexpressed in a number of solid tumors including pancreatic [3]. Evidence suggest that RR plays a positive role in tumor cell proliferation and metastasis as well as the development of resistance to nucleoside analogs used in PC chemotherapy, including gemcitabine [4]. High-level RRM1 expression correlates with poor responses to gemcitabine, which directly
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