去泛素化酶POH1调控结直肠癌相关成纤维细胞的生物学功能及其机制研究

肿瘤相关成纤维细胞（CAF）是构成肿瘤微环境的主要成分，在肿瘤的发生发展中起关键作用。然而，调控CAF生物学功能的关键基因和信号通路亟待阐明。我们在前期研究中，通过对结直肠癌临床标本的检测发现去泛素化酶POH1在结直肠癌CAF中低表达。功能实验显示，CAF中异常表达的POH1能够调节CAF的衰老相关分泌表型（SASP），重塑肿瘤微环境并影响结直肠癌的生长。机制上，POH1可能通过Caveolin-1/P38通路调控CAF的SASP因子的分泌。本项目拟在前期发现的基础上，利用CAF中POH1缺失小鼠的AOM/DSS肠癌模型等实验体系，深入探索POH1在CAF中的生物学功能及其影响结直肠癌发生发展的新机制。本项目将有助于从以下两个方面拓展结直肠癌的诊治策略：1）通过结直肠癌成纤维细胞中关键基因的表达水平提供肿瘤微环境新分型；2）利用CAF中的重要信号通路，干预CAF活性，从而抑制结直肠癌生长。

Cancer-associated fibroblasts (CAFs) are the preponderant cell population in tumor microenvironment. Emerging evidences suggest that CAFs play a critical role in promoting cancer development and progression. However, key molecular events that regulate CAFs remain unclear. Our preliminary experiments reveal that dysregulated function of POH1 in CAFs may influence CRC growth via modulating the strength of senescence-associated secretary phenotype (SASP). We found that human colorectal cancer (CRC)-associated fibroblasts exhibited lower POH1 expression than did the fibroblasts in the adjacent non-tumoral tissues. Additionally, functional assays indicate that POH1 in CAFs may have a tumor-suppressive function and contribute to the remodeling of microenvironment. Moreover, POH1 may alleviate SASP in CAFs through regulating Caveolin-1/P38 pathway. Intrigued by the pathological and functional significances of POH1 in CAFs, we set out to investigate molecular details underlying the effects of POH1 in CAFs on the growth of colorectal tumor, by using mice with specific deletion of POH1 in fibroblast cells, and the well-established AOM/DSS-induced CRC model. The present work will highlight a non-tumor autonomous function of POH1 in tumor development. The results may help to develop novel classification system based on gene expression in CAFs and therapeutic strategies that targeting CAF function.