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Role of chemokine receptor CXCR4 in sorafenib resistance of renal cell carcinoma

索拉非尼 CXCR4型 污渍 趋化因子受体 免疫组织化学 癌症研究 趋化因子 医学 化学 受体 病理 肝细胞癌 内科学 生物化学 基因
作者
Yi Bao,Bing Liu,Zhenjie Wu,Jiazi Shi,Tangliang Zhao,Anbang Wang,Hong Xu
出处
期刊:Chinese Journal of Urology 卷期号:38 (07): 531-536
标识
DOI:10.3760/cma.j.issn.1000-6702.2017.07.013
摘要

Objective To investigate the role and possible mechanism of Chemokine receptor CXCR4 in the drug resistance of sorafenib in renal cell carcinoma. Methods 786-O cells were inoculated into the anterior sciatic region of nude mice subcutaneously, 5×106 cells per point. The mice were given normal saline and sorafenib intragastric (80 mg/kg, 1 time/day) when the transplanted tumor volume reached about 100 mm3. The tumor volume in the saline group was more than 1 500 mm3 at the 5th week, and the tumor was taken as the control tissue. Sorafenib group tumors started to grow accelerately at week 8, and the tumor volume was more than 1 500 mm3 at week 13. The 13th week tumors were used as resistant tissue. The expression of CXCR4 in control tissues and drug resistant tissues was detected by real-time quantitative PCR, western blotting and immunohistochemistry. The pcDNA3.1-CXCR4 plasmid was constructed and transfected into 786-O cells. The expression of CXCR4 was detected by real-time quantitative PCR and western blotting. The drug reactivity of the cells was measured by CCK-8 and monoclonal assay to compare the drug resistance of the control group, CXCR4 overexpression group and CXCR4 overexpression + CXCR4 inhibitor AMD3100 group. The phosphorylation of PKB, ERK and STAT3 in the control group, the sorafenib alone group, the overexpressing CXCR4+ sorafenib group and the overexpressing CXCR4+ sorafenib+ AMD3100 group were determined by Western blotting. Results Compared with the control tissues, the mRNA levels of CXCR4 in the drug-resistant tissues increased (3.22±0.23) times, and the levels of protein expression increased (2.33±0.47) according to western blotting, the differences were statistically significant (P<0.01). After overexpression of CXCR4, the mRNA expression of CXCR4 increased (78.3±5.3) times, and the protein expression level increased (2.80±0.95) times, and the differences were statistically significant (P<0.01), indicating that the expression model was established successfully. The drug response curves of the control group, CXCR4 overexpression group and CXCR4 overexpression+ AMD3100 group on sorafenib were measured by cck8 method, and the IC50 was (7.5±0.8) μmol/L, (10.3±0.7) μmol/L, (5.7±0.6) μmol/L, the differences were statistically significant (P<0.05); The numbers of clones formed in the above three groups were 26±5, 56±12 and 42±9, respectively. The differences were statistically significant (P<0.05). Sorafenib could reduce the phosphorylation of PKB, ERK and STAT3, and overexpression of CXCR4 could reverse the inhibition of phosphatidylation of PKB, ERK and STAT3 by sorafenib. After inhibition of chemokine receptor CXCR4 activity by AMD3100, PKB, ERK, STAT3 phosphorylation was re-suppressed. Conclusions CXCR4 can promote renal cell carcinoma sorafenib resistance. The expression of CXCR4 increased in secondary resistant tumor tissue increased; CXCR4 may promote drug resistance by activating the cell viable pathway. The inhibition of CXCR4 signaling pathway is expected to improve the therapeutic effect of sorafenib in renal cell carcinoma. Key words: Renal cell carcinoma; Chemokine receptor CXCR4; Sorafenib; Drug resistant

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