Claudin-2 protects against colitis-associated cancer by promoting colitis-associated mucosal healing
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
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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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 9

In patients with IBD, colitis-associated CLDN2 upregulation is concentrated primarily in the regenerative crypts and correlates with Ki67 and Survivin expression.

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In patients with IBD, colitis-associated CLDN2 upregulation is concentra...
(A) In silico analysis of published transcriptome data from patients with IBD (55–65) (n = 360) demonstrating significantly upregulated CLDN2 expression compared with that in normal individuals (n = 153). (B and C) Immunohistochemical analysis of CLDN2 expression in biopsy samples from patients with IBD versus normal colon and intensity scoring. The pathological evaluation demonstrated significantly higher CLDN2 expression in the regenerative crypts (normal: n = 12; chronically injured crypts: n = 18; regenerative crypts: n = 21). (D–F) Coimmunofluorescence analysis of CLDN2 and Ki67 expression, along with in silico correlation analysis between CLDN2 and MKI67 in published data sets from patients with IBD (55–65) (n = 10/group). (G and H) Survivin and CLDN2 expression in IBD biopsy samples compared with normal samples (12/group). (I) In silico analysis of the correlation between CLDN2 and BIRC5 expression in published data sets from patients with IBD (55–65) (normal/IBD: n = 153/360). Data in C are presented as the mean ± SEM. *P < 0.05, ****P < 0.0001 by 1-way ANOVA with Tukey’s test. Data in E and H are presented as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed unpaired t test. Pearson’s correlation analysis was performed in F and I. Scale bar: 100 μM.