Thesis title: Role of KCASH2 and Hedgehog signaling pathway in Inflammatory Bowel Disease associated to Colorectal Cancer
The Hedgehog (Hh) pathway regulates intestinal stem cell renewal and differentiation, and its dysregulation contributes to several cancers, including inflammatory bowel disease (IBD)-related colorectal cancer (CRC). Among its inhibitors, KCASH2 acts as a tumor suppressor by promoting HDAC1 degradation, maintaining Gli1 acetylation, and repressing Hh signaling.
In silico analyses of ulcerative colitis-associated CRC patients revealed reduced KCASH2 expression and an inverse correlation with Gli1, suggesting a role for KCASH2 in disease progression. Using a KCASH2-KO mouse model combined with AOM/DSS treatment, we demonstrate that KCASH2 loss increases susceptibility to DSS-induced injury, as evidenced by higher mortality, severe weight loss, colon shortening, impaired epithelial recovery and diffuse immune cells infiltration. Consistently, KCASH2 deficiency was associated with enhanced NF-κB activation, impaired apoptotic clearance of damaged cells, and downregulation of epithelial and tight junction markers.
In vitro, KCASH2-silenced HT29 cells showed delayed wound closure under both basal and inflammatory conditions, confirming its role in epithelial regeneration.
At tumorigenic stages, KCASH2-KO mice developed more numerous, larger and higher grade dysplastic lesions than WT. Molecular analyses revealed Hh pathway hyperactivation, together with aberrant Wnt/β-catenin and Notch signaling and reduced ERK phosphorylation, indicating oncogenic network reprogramming. In conclusion, KCASH2 loss exacerbates inflammation, impairs epithelial repair, and promotes oncogenic signaling crosstalk, thereby accelerating IBD-related CRC. These findings identify KCASH2 as a key regulator of colonic homeostasis and a potential therapeutic target for inflammation driven tumorigenesis.