ARID1A缺陷型胃癌与放疗敏感性相关分子机制研究

In China gastric cancer has a high incidence and mortality.Radiation therapy is considered as a promising and standard treatment option for resectable gastric cancer,while the efficacy remains to be improved urgently. ARID1A deficiency is a common molecular alteration in gastric cancer and it plays a role in DNA damage response and DNA repair. Our recent preliminary studies show that, (1) ARID1A regulates checkpoint activation via controlling CHK2 protein stability. (2) ARID1A deficiency shifts the balance of DSB repair by promoting NHEJ repair and suppressing HR repair. (3) We observed radioresistance in ARID1A-deficient cells. The goal of the research proposed in this application is to,(1)Determine how ARID1A regulates CHK2 via its potential E3-ligase activity. (2)Determine how ARID1A dictates the choice of DNA repair pathway via regulating 53BP1 recruitment.(3)Test whether inhibiting aberrant checkpoint activation and NHEJ repair could represent a clinically applicable strategy for radiosensitization of gastric cancer.In summary, our goal of the research proposed in this application is to characterize the role of ARID1A in DNA damage response and DNA repair and to test a strategy for sensitizing ARID1A-deficient gastric cancer to radiation therapy.

中国胃癌发病率高，预后差，死亡率高。手术联合放疗是可根治胃癌患者的标准治疗手段，然而胃癌放疗疗效亟待提高。ARID1A基因缺陷是胃癌常见分子变异,在DNA损伤修复中发挥重要作用。本研究组前期研究已揭示，①ARID1A蛋白通过控制CHK2蛋白稳定性调节细胞周期检查点活化；②ARID1A缺陷通过增强NHEJ修复，削弱HR修复，调节DSB修复途径的平衡；③ ARID1A缺陷型细胞具有放疗抵抗性。根据前期研究结果，本课题拟进一步深入探索ARID1A在DNA损伤应答和DNA损伤修复中的作用机制，并从体内外研究水平，力求找到增加ARID1A缺陷型胃癌放射敏感性的分子靶点，通过进行个体化放射增敏靶向治疗，为提高胃癌放疗疗效提供新的治疗策略。

中国胃癌发病率高，预后差，死亡率高。手术联合放疗是可根治胃癌患者的标准治疗手段，然而胃癌放疗疗效亟待提高。ARID1A基因缺陷是胃癌常见分子变异,在DNA损伤修复中发挥重要作用。本次课题我们证实ARID1A缺失会影响CHK2表达，ARID1A缺失与CHK2高表达相联系，DNA损伤后，ARID1A的表达水平会影响CHK2激活，ARID1A缺失会影响细胞对放射线的敏感性，而在敲低CHK2后ARID1A缺陷型细胞对放射治疗敏感性增加，因此可采用CHK2抑制剂联合放疗治疗ARID1A缺陷型肿瘤。此外，我们发现CHK1抑制剂可增强PARP抑制剂BMN673对胃癌的疗效：使用siRNA抑制CHK1表达后，胃癌细胞系AGS和MKN1增殖能力及放射敏感性均显著降低。我们发现CHK1抑制剂LY2606368可导致DNA损伤，显著抑制胃癌细胞系AGS和MKN1增殖并诱导凋亡。此外，LY2606368可明显抑制同源重组修复，并在体内外实验中增强PARP抑制剂BMN673的抗肿瘤效应。