Cldn-7 deficiency promotes experimental colitis and associated carcinogenesis by regulating intestinal epithelial...

Area of Science:

• Gastroenterology and Oncology
• Molecular Biology
• Immunology

Background:

• The intestinal epithelial barrier is vital for preventing infection and injury.
• Chronic inflammation is a known risk factor for tumorigenesis.
• Claudin-7 (Cldn-7), a tight junction protein, is implicated in cell polarity, barrier integrity, inflammation, and tumor development, but its in vivo role in intestinal inflammation and colitis-associated colorectal cancer (CAC) remains unclear.

Purpose of the Study:

• To investigate the role of Claudin-7 (Cldn-7) in the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC) in vivo.
• To elucidate the mechanisms by which Cldn-7 deficiency affects intestinal homeostasis and disease progression.

Main Methods:

• Utilized inducible intestinal conditional Cldn-7 gene knockout mice (Cldn7fl/fl;villin-CreERT2).
• Established colitis and CAC models using azoxymethane (AOM) and dextran sodium sulfate (DSS) administration.
• Analyzed Cldn-7 expression in IBD and CAC models, assessing epithelial barrier integrity, inflammation, cell proliferation, and apoptosis.

Main Results:

• Cldn-7 knockout mice exhibited increased susceptibility to colitis and CAC, with exacerbated clinical symptoms and severe intestinal epithelial damage.
• Loss of Cldn-7 led to compromised epithelial barrier integrity, increased permeability, and heightened mucosal inflammation.
• Tumor burden and volume were significantly increased in Cldn-7 deficient mice following AOM/DSS treatment, associated with enhanced Wnt/β-catenin signaling pathway activation.

Conclusions:

• Claudin-7 (Cldn-7) plays a critical role in maintaining intestinal homeostasis and preventing inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC).
• Cldn-7 deficiency promotes colitis and malignant transformation by disrupting tight junction integrity and exacerbating inflammatory cascades.
• These findings highlight Cldn-7 as a potential therapeutic target for IBD and CAC.