Claudin-2 protects against colitis-associated cancer by promoting colitis-associated mucosal healing
Rizwan Ahmad, … , Punita Dhawan, Amar B. Singh
Rizwan Ahmad, … , Punita Dhawan, Amar B. Singh
Published October 10, 2023
Citation Information: J Clin Invest. 2023;133(23):e170771. https://doi.org/10.1172/JCI170771.
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Research Article Gastroenterology

Claudin-2 protects against colitis-associated cancer by promoting colitis-associated mucosal healing

Abstract

Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its role in CAC is not known. The current study was undertaken to examine the role for CLDN2 in CAC. The AOM/DSS-induced CAC model was used with WT and CLDN2-modified mice. High-throughput expression analyses, murine models of colitis/recovery, chronic colitis, ex vivo crypt culture, and pharmacological manipulations were employed in order to increase our mechanistic understanding. The Cldn2KO mice showed significant inhibition of CAC despite severe colitis compared with WT littermates. Cldn2 loss also resulted in impaired recovery from colitis and increased injury when mice were subjected to intestinal injury by other methods. Mechanistic studies demonstrated a possibly novel role of CLDN2 in promotion of mucosal healing downstream of EGFR signaling and by regulation of Survivin expression. An upregulated CLDN2 expression protected from CAC and associated positively with crypt regeneration and Survivin expression in patients with IBD. We demonstrate a potentially novel role of CLDN2 in promotion of mucosal healing in patients with IBD and thus regulation of vulnerability to colitis severity and CAC, which can be exploited for improved clinical management.

Authors

Rizwan Ahmad, Balawant Kumar, Ishwor Thapa, Raju Lama Tamang, Santosh K. Yadav, Mary K. Washington, Geoffrey A. Talmon, Alan S. Yu, Dhundy K. Bastola, Punita Dhawan, Amar B. Singh

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Figure 2

Cldn2 loss-of-expression promotes proinflammatory and proapoptotic transcriptional programs in mice subjected to colitis-associated cancer.

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Cldn2 loss-of-expression promotes proinflammatory and proapoptotic tran...
(A) Scatter plot depicting the comparative transcriptomic profile (RNA-Seq) between Cldn2KO and WT mice subjected to colitis-associated cancer (CAC) (n = 3/group). (B–D) KEGG pathway and GO biological function analysis based on differentially expressed genes (DEGs) in RNA-Seq analysis using colon RNA from AOM/DSS-treated Cldn2KO and WT mice (n = 3/group). (E) Heatmap showing selected DEGs (n = 3/group). (F–H) Immunoblotting and densitometric analysis of proteins involved in inflammation, proliferation, cell survival, and apoptosis in AOM/DSS-treated Cldn2KO and WT mice (n = 4/group). (I and J) Representative images of Ki67 and cleaved caspase-3 expression, and proliferation index (Ki67/cleaved caspase-3 expression) in AOM/DSS-treated mice (n = 4/group; 3 images/mice). (K) Graphical modeling representing the overall outcome of Cldn2KO mice when subjected to CAC. Data in G, H, and J are presented as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by 2-tailed unpaired t test. Scale bar: 100 μM.