PinX1/RBM10调控细胞端粒稳定介导食管鳞癌细胞放疗抵抗的机制研究

Radiotherapy has been widely used to treat esophageal squamous cell carcinoma (ESCC) patients in clinic. However, the mechanism by which ESCC responds or resist to radiotherapy remains unknown. Our preliminary results demonstrated that PinX1 induced cell resistance to RT through a new pathway of telomerase maintaining the telomere stability. We screened PinX1-interacting factors by mass spectrum and identified a new protein RBM10 (RNA binding motif protein 10). In addition, we found RBM10 could localize in Cajal body. It’s known that telomerase localizing in Cajal body is a critical step for telomerase achieving to telomere. These data indicated that PinX1/RBM10 may involve in telomerase transportation and regulate the therapeutic response of ESCC cells to radiation. However, the interaction mechanisms between PinX1 and RBM10 are still unclear. Therefore, based on these preliminary data, in this project we will investigate the impact of PinX1/RBM10 interactions on ESCC cells’ telomere stability and response to radiotherapy in vitro and in vivo. The success of this project will reveal the molecular mechanism by which PinX1/RBM10 interaction influences the ESCC cells’ therapeutic response to radiation. This study also will provide new supplementary information about the pathways of telomere maintenance. The study will bring about novel ideas and targets to optimize treatment strategies for ESCC patients in clinical settings.

放疗在食管鳞癌的综合治疗中占据核心地位，但辐射抗拒仍旧是限制放疗疗效的瓶颈。我们前期研究表明PinX1通过调控端粒酶的端粒募集维持端粒稳定并介导了食管鳞癌对放疗的抵抗，但机制不清。我们通过质谱筛选并鉴定出PinX1新的相互作用蛋白RBM10。RBM10可以定位于Cajal小体，端粒酶的Cajal小体定位是其移动到端粒的关键步骤。这些提示PinX1与RBM10相互作用可能通过参与端粒酶运输的调控来影响肿瘤细胞的端粒稳定，从而调节其放疗敏感性。基于这些重要发现，本立项将从分子、细胞、动物及组织水平探讨PinX1和RBM10相互作用对肿瘤细胞端粒稳定及放疗敏感性的影响及调控机制，研究将揭示PinX1/RBM10 影响食管鳞癌细胞放疗疗效的分子机制并丰富端粒酶/端粒的调控通路，为食管鳞癌病人的治疗提供新靶点、新思路。

申请者从事食管癌放疗抵抗及增敏的基础和临床研究。在本项目（NFSC: 81773235）的资助下主要研究端粒酶维持端粒稳定在食管癌放疗抵抗中的作用和机制，并在此基础上探讨电离辐射后食管癌免疫微环境的改变。研究发现，PinX1通过与RBM10的相互作用促进端粒酶催化亚基hTERT的Cajal小体定位和端粒运输，维持端粒及基因组的稳定并最终介导食管癌的放疗抵抗；端粒酶维持端粒稳定抑制cGAS-STING通路激活，食管癌组织中端粒酶的表达和效应T淋巴细胞的肿瘤微环境浸润呈负相关。在前期建立的转化研究模型的基础上，提出了PinX1/RBM10/TPP1协同调控恶性肿瘤端粒酶运输并发挥稳定端粒功能这一新的科学假设和研究方向，拟进一步深入探索，完善端粒酶/端粒调控在食管癌免疫耐受和放疗抵抗中的作用及分子机制的理论体系。标注本基金共发表论文4篇，基金执行期间，相关研究成果受邀在美国放射肿瘤学协会（ASTRO）第61届年会上做大会口头报告，获得多项中华医学会、中国医师协会、中国抗癌协会等学会重要任职，获得天津市科学技术进步一等奖一项（排名第五），获得安徽电视台2021“科普之星”称号。