RAB22A通过调控外泌体分泌促进结直肠癌化疗耐药的机制研究

Chemoresistance is not only related to tumor cells themselves, but also regulated by the interaction between cells. Exosomes are a class of nanoparticles that are secreted by cells transmitting information from cell to cell. RAB22A is a member of the RAB family of small GTPases that identified recently as an oncogene in the colorectal cancer (CRC) by our group. We revealed that RAB22A is associated with chemotherapeutic resistance, but the underlying mechanism remains unknown. Most intracellular transport pathways are controlled by the Rab family of small GTPases, and miRNAs are key signaling molecules in exosomes. Our recent data showed that up-regulated RAB22A is responsible for increased exosome secretion and associated with chemoresistance in CRC, and exosome-mediated intercellular transfer of special miRNAs from chemoresistant CRC cells allowed recipient cells to acquire chemoresistance phenotype. Thus, we hypothesize that RAB22A plays a role in exosome secretion in CRC, and may transfer chemoresistance property to recipient cells by delivering specific miRNAs. We expect to explore how CRC cells promote chemoresistance by cell-cell interaction. This study will provide new guidance and strategy for the therapy of CRC chemoresistance.

肿瘤化疗耐药不仅与肿瘤细胞自身有关，还受细胞间相互作用调控。外泌体是一类新型的介导细胞间通讯的微小囊泡。我们近期发现小G蛋白RAB22A在结直肠癌（CRC）中有促癌作用，并诱导化疗耐药，但其机理不明。已知RAB22A所属的Rab家族是囊泡转运的关键调控因子，而miRNA是外泌体中关键信号分子。我们预实验发现不同CRC细胞中RAB22A表达与其外泌体分泌能力及耐药指数呈正相关；耐药CRC细胞外泌体可携带特定miRNA进入其它CRC细胞使其获得耐药表型。我们据此提出假说：RAB22A通过某种机制促进CRC细胞外泌体分泌，从而运输更多特定miRNA进入其它CRC细胞，诱导其耐药。本项目拟在此基础上，阐明RAB22A调控外泌体分泌的机理，并进一步揭示分泌增加的外泌体通过miRNA调控CRC耐药的机制，从外泌体角度阐明CRC如何通过细胞间交流促进自身耐药，为CRC耐药防治提供新思路。

目前药物化疗仍然是结直肠癌（colorectal cancer, CRC）的主要治疗方式之一。耐药是阻碍化疗疗效的主要因素，然而目前对于化疗耐药的机制仍知之不多，研究CRC耐药机制具有重要的理论和临床价值。RAB22A是本课题组前期发现的一个新的候选癌基因，但其在肿瘤耐药中的角色尚不清楚。在本项目的资助下，本研究采用体外实验并结合临床标本分析，阐明RAB22A在CRC耐药中的作用，并进一步鉴定耐药CRC细胞外泌体中富集的miRNA，揭示CRC通过外泌体miRNA调控耐药的具体分子机制。本项目创新性地从外泌体角度阐明CRC细胞如何通过细胞间交流促进化疗耐药，有助于为CRC的化-疗耐药机制提供新的理论依据，并为逆转肿瘤耐药、改善预后提供新的思路和策略。