Chloride channel accessory 4 suppresses stem cell-like properties of colorectal cancer and enhances anti-PD-1 immunotherapyOA
Reduced chloride channel accessory 4(CLCA4)levels are linked to cancer development,while its role and mechanism in cancer stem cells(CSCs)remain unclear,In this study,we discovered that decreased CLCA4 expression was evident in CD133+CD44+colorectal CSCs and chemoresistant colorectal cancer(CRC)cells,Increased expression of CLCA4 inhibited the expression of stemness genes,reduced tumorsphere formation,suppressed the self-renewal,migratory,and invasive capabilities of colorectal CSCs in vitro,and suppressed the tumorigenicity of colorectal CSCs in vivo,Mechanistically,CLCA4 interacted with vimentin,leading to FAK pathway inactivation and subsequent suppression of CSC expansion,while vimentin up-regulation attenuated the effects of CLCA4 down-regulation and established its role in CLCA4-mediated colorectal CSC self-renewal,Decreased CLCA4 expression was positively correlated with colorectal CSC markers and vimentin in clinical specimens,Increased CLCA4 expression promoted the infiltration of cytotoxic CD8+T cells and enhanced the anti-PD-1 therapeutic efficacy,Our findings suggest that CLCA4 could impede colorectal CSC self-renewal by interacting with vimentin to suppress the FAK signaling pathway,potentially reducing tumor cell stemness and evading immune surveillance,The new findings on cellular and molecular mechanisms underpinning CRC development and progression could offer new perspectives for potential intervention and treatment of CRC.
Fang Wei;Qi Zou;Qihui Sun;Tingting Jiang;Tian Cai;Xiaojia Li;Keping Xie
Guangzhou Digestive Disease Center,Guangzhou First People''s Hospital and The Second Affiliated Hospital,South China University of Technology School of Medicine,Guangzhou 510180,China Center for Pancreatic Cancer Research,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,China Departments of Pathology and Immunology,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,ChinaGuangzhou Digestive Disease Center,Guangzhou First People''s Hospital and The Second Affiliated Hospital,South China University of Technology School of Medicine,Guangzhou 510180,China Center for Pancreatic Cancer Research,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,China Departments of Pathology and Immunology,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,ChinaCenter for Pancreatic Cancer Research,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,China Departments of Pathology and Immunology,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,ChinaCenter for Pancreatic Cancer Research,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,China Departments of Pathology and Immunology,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,ChinaCenter for Pancreatic Cancer Research,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,China Departments of Pathology and Immunology,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,ChinaCenter for Pancreatic Cancer Research,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,China Departments of Pathology and Immunology,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,ChinaGuangzhou Digestive Disease Center,Guangzhou First People''s Hospital and The Second Affiliated Hospital,South China University of Technology School of Medicine,Guangzhou 510180,China Center for Pancreatic Cancer Research,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,China Departments of Pathology and Immunology,The South China University of Technology School of Medicine,Guangzhou,Guangdong 510006,China
医药卫生
Cancer stem cellCLCA4Colorectal cancerImmunotherapyVimentin
《Genes & Diseases》 2026 (3)
P.442-455,14
supported by the National Natural Science Foundation of China(No.81972780)the Natural Science Foundation of Guangdong Province,China(No.2020A1515010051).
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