Cadherin 11-mediated juxtacrine interaction of gastric cancer cells and fibroblasts promotes metastasis via YAP/tenascin-C signaling  

CDH11介导的胃癌细胞和成纤维细胞近分泌信号激活YAP/TNC轴促进胃癌转移

作　　者：Jiaojiao Ni Mingchun Jiang Yanyan Chen Xianping Rao Junjie Jiang Zizhen Zhang Fangyu Ju Dongyang Guo Boya Wang Lisong Teng Liangjing Wang Tianhua Zhou Wei Zhuo 倪娇娇;姜明春;陈艳妍;饶显平;姜钧杰;张子震;琚方玉;郭东阳;王博雅;滕理送;王良静;周天华;卓巍(Department of Cell Biology and Department of Gastroenterology,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou 310016,China;Department of Gastroenterology,The Second Affiliated Hospital Zhejiang University School of Medicine,Hangzhou 310002,China;Cancer Center,Zhejiang University,Hangzhou 310058,China;Institute of Gastroenterology,Zhejiang University,Hangzhou 310002,China;Department of Surgical Oncology,The First Affiliated Hospital Zhejiang University School of Medicine,Hangzhou 310002,China;Department of Molecular Genetics,University of Toronto.Toronto ON M5S 1A8.Canada)

机构地区：[1]Department of Cell Biology and Department of Gastroenterology,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou 310016,China [2]Department of Gastroenterology,The Second Affiliated Hospital Zhejiang University School of Medicine,Hangzhou 310002,China [3]Cancer Center,Zhejiang University,Hangzhou 310058,China [4]Institute of Gastroenterology,Zhejiang University,Hangzhou 310002,China [5]Department of Surgical Oncology,The First Affiliated Hospital Zhejiang University School of Medicine,Hangzhou 310002,China [6]Department of Molecular Genetics,University of Toronto.Toronto ON M5S 1A8.Canada

出　　处：《Science Bulletin》2022年第10期1026-1030,M0003,共6页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(81972276,31771540,82173040,91740205,and 31620103911);Natural Science Foundation of Zhejiang Province(LYY19H310011);Fundamental Research Funds for the Central Universities(2021QNA7004)。

摘　　要：Gastric cancer(GC)is the fifth most common cancer and the third leading cause of cancer-related death worldwide[1],Metastasis is the leading cause of GC mortality.The complex dynamic interactions between tumor cells and stromal cells in the tumor microenvironment are crucial for tumor metastasis.Many secreted cytokines have been well documented to mediate the crosstalk between tumor cells and stromal cells in a paracrine manner[2].However,how the juxtacrine signals transduced by adjacent cellcell adhesion modulate cancer metastasis has yet to be elucidated[3].As one of the most important cell-cell adhesion molecules,the classical cadherin superfamily also initiates different intracellular signaling cascades and regulates cytoskeletal dynamics,permeability,cell polarity,and tumor progression[4,5].肿瘤细胞与基质微环境的相互作用调控肿瘤转移.肿瘤相关成纤维细胞(CAFs)是肿瘤微环境的主要细胞群,以往报道CAFs通过异常旁分泌信号传导促进肿瘤转移,而CAFs与相邻胃癌细胞是否利用近分泌信号(juxtacrine)促进转移尚不清楚.Cadherins家族(钙黏附蛋白)介导细胞间黏附作用.本文利用TCGA数据库系统研究Cadherins家族,筛选发现cadherin 11(CDH11)在胃癌中表达上调且与预后和分期显著相关,且CDH11表达水平与CAFs主要标志物紧密关联.CDH11介导了CAFs与胃癌细胞之间的黏附互作,从而促进胃癌细胞迁移、克隆形成和肺转移等恶性行为.机制上,CAFs通过CDH11介导的近分泌作用激活胃癌细胞YAP信号通路,上调TNC表达,从而增强胃癌细胞恶性表型.另外,胃癌临床样本数据表明,CDH11,YAP和TNC之间的表达水平显著相关,且CDH11和TNC与胃癌患者不良预后显著相关.该研究揭示了CDH11-YAP-TNC轴在CAFs与胃癌细胞近分泌信号中的作用,为胃癌转移的临床治疗和预后提供了潜在的靶点.

关 键 词：CDH1 肿瘤微环境 胃癌转移 恶性行为 肿瘤转移 胃癌患者 胃癌细胞 成纤维细胞 

分 类 号：R735.2[医药卫生—肿瘤]