Chinese Clinical Oncology

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Chemokine CX3CL1/CX3CR1 biological axis promote ovarian cancer cell apotosis induced by platinum drug

LIU Hongmei,LI Mengdi, MAO Yannan, HUANG Yongzhi, LIU Yingzhao, LI Li, WANG Qi.   

  1. Research Department, Affiliated Cancer Hospital of Guangxi Medical University, Nanning 530021,China
  • Received:2016-01-23 Revised:2016-03-23 Online:2016-05-31 Published:2016-05-31
  • Contact: WANG Qi

Abstract: Objective To study the relationship between the chemokine CX3CL1/CX3CR1 and platinum drug resistance, as well as prognosis in ovarian cancer patients. To dynamically detect the resistance nude mice model of CX3CL1 and its receptor CX3CR1 in the course of platinum resistance. To analyze the expression of CX3CL1, CX3CR1 and the correlation of Fas signaling pathway. Methods The cancer gene atlas(TCGA) database of patients with ovarian cancer genomewide expression was employed to analyze the relationship of CX3CL1/CX3CR1 in platinum sensitivity or resistant patients with clinical features. Ovarian cancer SKOV3 sensitive cells(SKOV3-GFP) with green fluorescent marker and cisplatin resistant cells(SKOV3-GFP/DDPⅢ) were subcutaneously injected in nude mice. After xenograft was constracted, cisplatin was intraperitoneally injected. Real time fluorescence quantitativePCR(qRT-PCR) was used to detect the expression of CX3CL1, CX3CR1 and genes on Fas signal pathway after 0, 2, 5, 8 times of cisplatin injection.Results CX3CL1 expression was negatively correlated with FIGO and platinum resistance(r=-0.112,P=0.030;r=-0.106,P=0.044), CX3CR1 expression was negatively correlated with progression-free survival time(r=-0.130,P=0.029) and positively correlated with 1-year relapse rate(r=0.119,P=0.045). The average expression of CX3CL1 in platinum sensitive group was 3.96±0.039, higher than 3.64±0.55 of platinum resistant group(P=0.000). After the intervention of cisplatin, xenograft grew gradually. The weight of xenograft in SKOV3-GFP/DDPⅢ group was higher than SKOV3GFP group, and xenograft in the both two groups shrank at the fifth time of infection. After cisplatin stimulation, the expression of CX3CL1/CX3CR1 in SKOV3GFP group increased significantly(P=0.001, P=0.002), but it remained low in SKOV3-GFP/DDPⅢ group. The expression of Fas and FADD of Fas signal pathway in SKOV3-GFP/DDPⅢ group was also significantly lower than them in SKOV3-GFP group(P<0.001). However, PARP1 gene significantly rose in SKOV3-GFP/DDPⅢ group than that in SKOV3-GFP group(P<0.001). The expression of CX3CL1 and CX3CR1 was positively correlated with Fas and FADD, while it was negatively correlated with PARP1 of Fas signaling pathways. Conclusion The down-regulation of CX3CL1 and CX3CR1 is associated with platinum resistance. They may play a role in maintain the sensitivity of tumor cells to platinum. The low expression of CX3CL1 and CX3CR1 may suppress Fas signal pathway through some mechanism, resulting in transduction disorder, inhibiting cell apoptosis and inducing platinum resistance of ovarian cancer. The lower expression of drugresistant cells may be a mechanism inhibiting Fas signaling pathways, which make its conduction misbalance, finally inhibiting cell apoptosis, inducing the resistance of ovarian cancer. It may be a platinum promote ovarian cancer therapy targeting molecules.

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