PARP-1抑制剂对XRCC2缺陷性直肠癌放疗增敏作用及机制研究

Rectal cancer is one of the most common malignant tumors in China and radiotherapy remains one of the main treatment modality for advanced rectal cancer. However, radioresistance is a major obstacle to the efficient radiation therapy and contributes significantly to treatment failure, highlighting the need for the development of novel radiosensitizers that can be used to overcome tumor radioresistance and, thus, improve the efficacy of radiotherapy. PARP-1 inhibitors can specifically inhibit DNA injury repair process and bring promise for individualized cancer treatment.Our previous study showed that rectal cancer cell with low expression of XRCC2 displayed increased sensitivity to olaparib, one PARP-1 inhibitor, and when XRCC2-deficient cancer cells were pretreated with olaparib then exposed to X-ray irradiation, the G2/M phase were significantly arrested at 24h post-irradiation. Therefore, we hypothesized that low expression of XRCC2 may hamper the DNA repair process, resulting in increased sensitivity to olaparib. However,the molecular mechanisms for increased sensitivity of XRCC2-deficient cells to radiotherapy remain elusive nowadays. Our research proposal aims to determine the increased sensitivity of XRCC2-deficient cells to radiotherapy in terms of molecules, cell and animal model and elucidate the molecular mechanisms of the sensitization of oloaparib. Our study will provide direct evidence of the clinical use of PARP-1 inhibitors as radiosensitizers in XRCC2-deficient rectal cancer cases and may provide novel approaches for targets radiosensitization of rectal cancer.

直肠癌是我国最常见的恶性肿瘤之一。放疗是进展期直肠癌主要的治疗方法之一，但直肠癌放疗抵抗是制约其疗效提高的主要因素，肿瘤靶向放射增敏是解决这一问题有效方法。PARP-1抑制剂作为靶向DNA损伤修复抑制剂，给肿瘤个体化治疗带来新的希望。我们前期研究发现 XRCC2低表达的结直肠癌细胞系对PARP-1抑制剂(olaparib)敏感，进一步通过olaparib联合放疗发现XRCC2缺陷性直肠癌细胞DNA损伤修复延迟，细胞周期阻滞阻于G2/M期，因此我们认为 olaparib对XRCC2缺陷性直肠癌细胞有放射增敏作用，但具体的分子机制仍不清楚。本课题拟在此基础上从分子、细胞和动物水平明确olaparib对XRCC2缺陷性结直肠癌细胞有特异性的放射增敏效应，并阐明其可能的增敏机制。旨在获得PARP-1抑制剂作为XRCC2缺陷型直肠癌特异性放疗增敏剂的直接证据，为直肠癌靶向放疗增敏提供新方法。

放化疗是进展期直肠癌主要的治疗方法之一，但直肠癌放化疗抵抗是直肠癌治疗过程中的医学难题，肿瘤靶向放射增敏是解决这一问题有效方法。本课题通过体外细胞模型和体内动物模型研究PARP1抑制剂Olaparib的放疗增敏效应及其分子机制。主要结果：XRCC2在直肠癌组织中的表达明显高于配对的癌旁组织，且与肿瘤大小、肿瘤T分期、M分期、TNM分期、Duke's分期、淋巴结转移等等临床病理特征及预后密切相关；下调XRCC2的表达可抑制5FU诱导的SW480细胞DNA损伤修复，导致细胞G2/M期阻滞和凋亡增加，表明XRCC2在进展期直肠癌中的表达水平与化疗抵抗相关。体内外实验显示Olaparib可提高直肠癌细胞对放疗的敏感性，尤其是对XRCC2缺陷的SW480细胞有显著增敏放疗作用。Olaparib联合X射线照射可以导致XRCC2缺陷的SW480细胞发生G2/M期阻滞，抑制细胞增殖及DNA损伤修复；Olaparib增敏XRCC2缺陷的直肠癌细胞放疗的机制可能是通过激活人直肠癌细胞P53-P21通路蛋白，进一步诱导肿瘤细胞衰老导致。这些结果提示XRCC2是预测直肠癌放化疗敏感性的生物标志物，获得了Olaparib作为XRCC2缺陷型直肠癌特异性放疗增敏剂的直接证据，为直肠癌的放射治疗提供新的思路。