POLI作为食管癌放射治疗新靶点的实验研究

It is great significant to improve the efficacy of radiotherapy on esophageal cancer through reversing the radio-resistance of cancer cells. Many strategies have been developed to overcome the radio-resistance of cancer cells, but their effects are unsatisfied. Translesion DNA synthesis, an emergency approach of cells to repair damaged DNA, is completed by interaction of multiple DNA polymerases. Recent study suggests that translesion DNA synthesis polymerases play important roles in the radio-resistance of cancer cells. Our preliminary studies have shown that POLI, an essential polymerase in translesion DNA synthesis, is significantly unregulated through transcriptional regulation of Sp1 and other transcription factors in the esophageal cancer tissues, and associated with radio-resistance of esophageal cancer cells. Thus, targeting for POLI may increase radiosensitivity of esophageal cancer cells. In this project, cell lines expressing different levels of POLI from human esophageal cancer cells will be established via the molecular biology approach. With these cell lines, the mechanism by which POLI mediates radio-resistance will be explored through translesion DNA synthesis pathway. Meanwhile, clofibrate, one of PPARα agonists, will be used as an agent, which inhibits the binding between POLI DNA promoter and Sp1/ HIF-1α, and reverses POLI-mediated radio-resistance of esophageal cancer cells. The result of this project may reveal the new mechanism for radio-resistance of esophageal cancer cells, and provide a novel strategy to improve the outcome of radiotherapy for esophageal cancers.

逆转食管癌细胞放射抗拒性对于提高食管癌放疗疗效意义重大。目前克服肿瘤细胞放射抗拒性策略较多,但效果欠佳。跨损伤DNA合成途径是在多种DNA聚合酶等共同作用下完成的细胞应急修复机制，最新研究表明:该途径DNA聚合酶与肿瘤细胞放射抗拒性关系密切。POLI是跨损伤DNA合成途径一个重要聚合酶,前期研究中我们发现食管癌组织中POLI在Sp1等多种转录因子共同激活下表达显著上调，并增加食管癌细胞对放射线的抵抗。因此，抑制POLI表达有助于逆转食管癌细胞的放射抗拒性。本项目拟通过分子生物学手段建立POLI不同表达水平的食管癌细胞株，从跨损伤DNA合成途径研究POLI致食管癌细胞放射抗拒性的机制；同时拟使用PPARα激动剂氯贝特抑制Sp1和HIF-1α与POLI启动子DNA的结合，逆转POLI引起的食管癌放射抗拒性。本项目的研究成果将有望从新角度揭示食管癌放射抗拒性机理，为食管癌放射增敏提供一种新方法。

逆转食管癌细胞放射抗拒性和转移对于提高食管癌治疗疗效意义重大。目前克服肿瘤细胞放射抗拒性和转移策略较多,但效果欠佳。跨损伤DNA合成途径是在多种DNA聚合酶等共同作用下完成的细胞应急修复机制，最新研究表明:该途径DNA聚合酶与肿瘤细胞放射抗拒性关系密切,能够引起DNA的突变。Pol ι是跨损伤DNA合成途径一个重要聚合酶,我们的研究数据表明：食管癌组织中Pol ι的表达显著上调，并增加食管癌细胞对放射线的抵抗，影响食管癌术后放疗患者的预后；PPARα激动剂非诺贝特可提高食管癌细胞放射敏感性；同时，我们亦发现Pol ι通过活化JNK-AP-1信号通路诱导EMT相关分子表达，促进食管癌细胞转移。临床标本提示，Pol ι过表达与食管癌患者的不良预后相关。综上，Pol ι可能是预测食管癌患者预后的分子标志物及治疗食管癌的靶点。