非小细胞肺癌中ARID2突变与靶向干预HSPA1A的协同致死效应及机制研究

Chromatin remodeling, a type of epigenetic mechanisms, is known to play important roles in multiple biological processes. Aberrant chromatin remodeling alters chromatin structure and gene expression, which gives rise to diverse diseases, such as cancer. Recent research shows that .somatic mutations of ARID2, a SWI/SNF subunit, are observed in about 5~7% of human non-small cell lung cancer (NSCLC) by genome sequencing, however, the mechanism of ARID2 loss-of-function mutation promoting cancer development is still unclear. Our ongoing research found that low ARID2 expression was significantly associated with poor patient survival. We further comparatively analyzed the gene transcriptional expression of ARID2 wild type and mutant lung tumors, and found ARID2 mutant tumors expressed higher level of HSPA1A..Targeting HSPA1A selectively inhibited ARID2 mutant tumors, but had no effect on ARID2 wild type ones. Therefore, this project focuses on ARID2 mutation, and discusses the role and mechanisms of ARID2 in NSCLC development, and reveals synthetic lethality by targeting HSPA1A in ARID2-deficient NSCLC. This will provide a theoretical and experimental basis for elucidating the pathological mechanism of ARID2 mutation promoting tumors and discovering new intervention strategies.

染色质重塑是一种重要的表观遗传调控机制，参与调控许多重要生物过程。染色质重塑异常将影响染色质结构和基因表达进而引起多种疾病如肿瘤等的发生。近年来通过基因组测序方法发现SWI/SNF染色质重塑复合物组分ARID2在非小细胞肺癌中突变率达到5~7%，然而ARID2突变促肿瘤的机制不甚清楚。本项目前期研究工作发现低表达ARID2的非小细胞肺癌患者预后差；进一步比较ARID2野生型与突变型肿瘤的基因表达谱，发现ARID2突变型肿瘤高表达热休克蛋白HSPA1A，并且靶向干预HSPA1A能够协同致死ARID2突变型肿瘤，而对ARID2野生型肿瘤没有影响。为此，本项目将以ARID2突变为切入点，揭示其在非小细胞肺癌发生发展中的作用，并探讨ARID2失活突变与靶向干预HSPA1A的协同致死效应及机制。这将为阐明ARID2突变促肿瘤的病理机制，发现关键干预靶点形成治疗新策略提供理论依据和实验基础。

染色质重塑基因ARID2在肺腺癌中的失活突变率约达7%，然而，ARID2在肺腺癌发生发展中的功能尚不清楚。我们发现在人和小鼠肺腺癌发生发展过程中，ARID2表达水平会逐渐降低。利用基于KrasG12D的原发肺癌小鼠模型发现，敲除ARID2会显著加速肺腺癌的恶性进展，体外细胞实验显示敲低ARID2促进人和小鼠肺癌细胞的增殖，提示ARID2扮演抑癌基因的角色。机制分析发现，ARID2主要通过结合在HSPA1A启动子区来抑制HSPA1A基因转录，从而发挥其抑癌基因的功能。我们进一步发现，抑制HSPA1A可以特异性地抑制ARID2缺陷型肺腺癌的恶性进展。我们的研究不仅揭示了ARID2是负向调控肺腺癌恶性进展的重要基因，而且提示HSPA1A有望成为ARID2缺陷型肺腺癌的潜在治疗靶标。