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.

中文翻译：

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Claudin-2 通过促进结肠炎相关粘膜愈合来预防结肠炎相关癌症

炎症性肠病 (IBD) 患者容易患结肠炎相关癌症 (CAC)。慢性炎症会增加 CAC 的风险。相反，粘膜愈合预示着 IBD 预后的改善和 CAC 风险的降低。然而，结肠炎、粘膜愈合和 CAC 之间的分子整合仍知之甚少。IBD 中 Claudin-2 (CLDN2) 表达上调；然而，它在 CAC 中的作用尚不清楚。目前的研究旨在探讨 CLDN2 在 CAC 中的作用。AOM/DSS 诱导的 CAC 模型用于 WT 和 CLDN2 修饰小鼠。为了增加我们对机制的理解，采用了高通量表达分析、结肠炎/恢复的小鼠模型、慢性结肠炎、离体隐窝培养和药理学操作。与 WT 同窝小鼠相比，Cldn2 KO小鼠尽管患有严重结肠炎，但仍显示出对 CAC 的显着抑制。Cldn2缺失还会导致结肠炎的恢复受损，并且当小鼠通过其他方法遭受肠道损伤时，损伤会增加。机制研究表明 CLDN2 在 EGFR 信号传导下游和通过调节 Survivin 表达促进粘膜愈合方面可能具有新作用。CLDN2 表达上调可防止 IBD 患者免受 CAC 影响，并与隐窝再生和生存素表达呈正相关。我们证明了 CLDN2 在促进 IBD 患者粘膜愈合方面的潜在新作用，从而调节结肠炎严重程度和 CAC 的脆弱性，可用于改善临床管理。