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CMTM3 Promotes Colitis-associated Carcinogenesis via CLTC Stabilization and Modulation of VE-cadherin
Rongbin Li1, Yuan Liu1, Qiyao Liu2
1Department of Immunology, School of Basic Medical Sciences and NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China; Peking University Center for Human Disease Genomics, Beijing, China.
Background & Aims:
Inflammatory bowel disease leads to increased risk of developing colitis-associated colon cancer (CAC). CMTM3 has a higher methylation level in colon cancer, and accumulating evidence suggests that chemokine-like factor-like MARVEL transmembrane domain-containing member 3 (CMTM3) participates in inflammation and cancer development.
Methods:
We explored the signs of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC in wild-type (WT) and Cmtm3 deficiency (Cmtm3-/-) mice. Experimental colitis was induced in Cmtm3-/- mice as well as mice with endothelial cell-specific deletion of Cmtm3. Disease phenotypes were investigated by body weight, disease activity index (DAI), colon length, histology, immune cell infiltration, and intestinal permeability. The mechanism was analyzed using bone marrow reconstitution, immunofluorescent staining, Western blot, immunoprecipitation, and pull-down experiments.
Results:
We found CMTM3 promoted CAC by aggravating colitis. Further, we revealed endothelial cell-specific deletion of Cmtm3 inhibited the colitis development. In vitro and in vivo mechanistic studies revealed that CMTM3 drove colitis by increasing clathrin-dependent downregulation of vascular endothelial-cadherin, thus causing vascular permeability. We further identified that CMTM3 interacted with clathrin heavy chain and inhibited clathrin heavy chain ubiquitination and proteasome-dependent degradation. Interestingly, Cmtm3 knockout and imatinib mesylate both targeted vascular permeability and had comparable efficacy.
Conclusions:
Our study indicates that CMTM3 promotes CAC by aggravating colitis through causing vascular permeability, providing insights into targets for development of future therapies.
