PARPi通过抑制XRCC1的表达增加食管鳞癌放射治疗敏感性  

PARPi increases radiotherapy sensitivity of esophageal squamous cell carcinoma by inhibiting XRCC1 expression

作　　者：李祎萍 张予菲 孙光志 叶蕴瑶 沈小舟 韩高华 LI Yiping;ZHANG Yufei;SUN Guangzhi;YE Yunyao;SHEN Xiaozhou;HAN Gaohua(Department of Oncology,Taizhou people’s Hospital affiliated to Nanjing Medical University,Taizhou 225300,China;Radiotherapy Center,Taizhou people’s Hospital affiliated to Nanjing Medical University,Taizhou 225300,China)

机构地区：[1]南京医科大学附属泰州人民医院肿瘤科,泰州225300 [2]南京医科大学附属泰州人民医院放疗中心,泰州225300

出　　处：《辐射研究与辐射工艺学报》2023年第3期44-52,共9页Journal of Radiation Research and Radiation Processing

基　　金：江苏省“六个一工程”课题(LGY2019038);泰州市“311工程”课题(RCPY201813)资助。

摘　　要：探讨PARP抑制剂(PARPi)对XRCC1的表达以及对食管鳞癌(ESCC)放射治疗敏感性的影响。收集接受直线加速器辐照治疗的ESCC患者组织标本,免疫组化法检测其中XRCC1、PARP-1表达,观察其表达对ESCC患者放疗近期疗效的影响。ECA109细胞经AZD2281(PARP抑制剂)处理后接受加速器辐照,检测PARPi的放疗增敏比(SER)。利用RT-PCR实验检测AZD2281联合辐照后XRCC1mRNA转录情况,探讨PARPi对辐照后ECA109细胞XRCC1mRNA转录的影响。结果发现,XRCC1阳性者放疗的客观有效率(ORR)低于阴性者(38.1%vs.88.9%,p=0.017);PARP-1阳性者放疗的ORR低于阴性者(36.8%vs.81.8%,p=0.026)。AZD2281的浓度为3μmol/L时,联合组的SER=1.744。AZD2281可增强ECA109细胞的辐射损伤作用。辐射后48 h XRCC1mRNA相对表达量明显上升;联合PARPi可抑制辐射诱导的XRCC1mRNA表达上调。本组结果显示,XRCC1、PARP-1高表达者放疗近期疗效较差,放疗可诱导XRCC1基因转录,AZD2281能有效抑制辐射诱导的XRCC1 mRNA表达上调,其可能的机制是PARPi抑制DNA-PKcs进而下调XRCC1表达。该结果提示PARPi可能通过抑制XRCC1表达、减少DNA损伤修复,从而增加ESCC放疗敏感性。This study investigated the effect of poly-ADP ribose polymerase inhibitor(PARPi)on X-ray repair cross complementing 1 gene(XRCC1)expression and radiotherapy sensitivity of esophageal squamous cell carcinoma(ESCC).Tissue samples from patients with ESCC treated with irradiation using a linear accelerator were collected to detect the expression of XRCC1 and PARP-1 with immunohistochemical staining,and the effect of their expression on radiotherapy efficacy was evaluated.A linear accelerator was used to irradiate ECA109 cells after treatment with different concentrations of AZD2281(a PARP inhibitor)to detect the radiotherapy sensitization ratio(SER)of PARPi.An RT-PCR assay was used to assess the relative expression of XRCC1 mRNA in ECA109 cells treated with irradiation and AZD2281 and to explore the effect of PARPi on the transcription of the XRCC1 gene in ECA109 cells after irradiation.Our data indicated that the objective response rate(ORR)of XRCC1-positive patients was lower than that of XRCC1-negative patients(38.1%vs.88.9%,p=0.017),while the ORR of PARP-1-positive patients was lower than that of PARP-1-negative patients(36.8%vs.81.8%,p=0.026).The SER of the cells treated with irradiation and AZD2281 at a concentration of 3 mmol/L was 1.744,implying that AZD2281 can enhance the irradiation damage of ECA109 cells.The relative expression level of XRCC1 mRNA increased significantly at 48 h after irradiation;however,when combined with PARPi,the radiation-induced up-regulation of XRCC1 mRNA was inhibited.The results of this study showed that patients with ESCC with a high expression of XRCC1 and PARP-1 display poor short-term radiotherapy efficacy and that irradiation can induce XRCC1 gene transcription.AZD2281 effectively inhibited the radiation-induced up-regulation of XRCC1 expression and increased the radiosensitivity of ECA109 cells.A possible mechanism is that PARPi inhibited DNA-PKcs and then down-regulated XRCC1 expression.These results suggest that PARPi may increase the radiotherapy sensitivity of patients

关 键 词：食管鳞癌 放射敏感性 聚(腺苷二磷酸核糖)聚合酶抑制剂 X射线损伤修复基因-1 

分 类 号：R735[医药卫生—肿瘤]