XRCC2 has been shown to increase the radioresistance of some cancers. Here, XRCC2 expression was investigated as a predictor of preoperative radiotherapy (PRT) treatment response in locally advanced rectal cancer (LARC). XRCC2 was found to be overexpressed in rectal cancer tissues resected from patients who underwent surgery without PRT. In addition, overall survival for LARC patients was improved in XRCC2-negative patients compared with XRCC2-positive patients after treatment with PRT (P < 0.001). XRCC2 expression was also associated with an increase in LARC radioresistance. Conversely, XRCC2-deficient cancer cells were more sensitive to irradiation in vitro, and a higher proportion of these cells underwent cell death induced by G2/M phase arrest and apoptosis. When XRCC2 was knocked down, the repair of DNA double-strand breaks caused by irradiation was impaired. Therefore, XRCC2 may increases LARC radioresistance by repairing DNA double-strand breaks and preventing cancer cell apoptosis. Moreover, the present data suggest that XRCC2 is a useful predictive biomarker of PRT treatment response in LARC patients. Thus, inhibition of XRCC2 expression or activity represents a potential therapeutic strategy for improving PRT response in LARC patients.
BackgroundAnalysis using publicly available algorithms predicts that X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2), a key component in the homologous recombination repair pathway, is a potential target of micro-ribonucleic acid-7 (miR-7). Some studies have shown that both miR-7 and XRCC2 are associated with cancer development. For this purpose, we searched for the possible relationship between miR-7 and XRCC2 in the development of colorectal cancer (CRC).MethodsmiR-7 expression was assessed in CRC specimens and cell lines using real-time polymerase chain reaction (PCR). Luciferase reporter assay was used to confirm the target associations. The effect of miR-7 on cell proliferation and apoptosis was confirmed in vitro by the methylthiazol tetrazolium (MTT) assay, colony formation assay, and flow cytometry. Gene and protein expression were examined using real time PCR and western blotting, respectively.ResultsmiR-7 was downregulated in CRC specimens and cell lines, and targeted the 3′ untranslated region of XRCC2. miR-7 overexpression reduced cyclin D1 expression and increased p21, caspase-3, and BAX expression, which subsequently inhibited CRC cell proliferation and induced CRC cell apoptosis. However, XRCC2 can repress the inhibitory effects of miR-7 on proliferation.ConclusionOur findings suggest that miR-7 plays a protective role by inhibiting proliferation and increasing apoptosis of CRC cells. It may identify new targets for anti-cancer treatment.
Drug-resistant cancer cells exhibit increased glycolysis, and targeting glycolysis is considered as a novel strategy to overcome drug resistance. Polypyrimidine tract-binding protein (PTBP1) has been found to be a regulator of glycolysis, however, the role of PTBP1 in drug resistance remains to be elucidated. Herein, we found that PTBP1 was highly expressed in two drug-resistant colon cancer cell lines, vincristine-resistant HCT-8 cell line (HCT-8/V) and oxaliplatin-resistant HCT116 cell line (HCT116/L-OHP). The levels of glucose consumption and lactate production as well as expression of pyruvate kinase M2 isoform (PKM2) and hexokinase II (HK2) were elevated, while PKM1 level was reduced in HCT-8/V and HCT116/L-OHP cells when compared with the HCT-8 and HCT116 cells. PTBP1 knockdown enhanced the sensitivity of HCT-8/V and HCT116/L-OHP cells to vincristine and oxaliplatin, and caused reduction in glucose consumption and lactate production. PKM2 expression, but not HK2, was decreased and PKM1 expression level was increased in cells transfected with si-PTBP1. In addition, PTBP1 overexpression significantly induced glycolysis and reduced drug sensitivity, whereas the effects were attenuated by si-PKM2. Treatment with 2-deoxyglucose (2-DG) also attenuated the effect of PTBP1 overexpression on drug sensitivity. In conclusion, PTBP1 knockdown enhanced the sensitivity of drug-resistant colon cancer cells to vincristine and oxaliplatin through repression of glycolysis. Our study provided a promising therapeutic strategy to overcome drug resistance in colon cancer cells.
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