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 Cldn2 KO 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.

Identification of claudin-2 as a promising biomarker for early diagnosis of pre-diabetes

“…Research on CLDN2 has primarily focused on gastrointestinal diseases, due to its role as a member of the tight junction protein family, prompting extensive investigation into its role about the intestinal barrier ( Beggs et al, 2023 ; Ganapathy et al, 2023 ; Rini et al, 2023 ). Numerous studies have progressively affirmed its association with inflammatory bowel diseases ( Raju et al, 2020 ; Ahmad et al, 2023 ; Alghamdi and Al-Zahrani, 2023 ). Besides, researches on the association between CLDN2 and cancer has been steadily increasing ( Piontek et al, 2020 ), with a growing evidence elucidating its involvement in tumor growth, metastasis, and metabolism ( Eguchi et al, 2021 ; Hirota et al, 2021 ; Tabaries et al, 2021 ; Wei et al, 2021 ).…”