Transforming Growth Factor Beta Promotes Inflammation and Tumorigenesis in Smad4-Deficient Intestinal Epithelium in a YAP-Dependent Manner.

ABSTRACT

Transforming growth factor beta (TGF-ß), a multifunctional cytokine, plays critical roles in immune responses. However, the precise role of TGF-ß in colitis and colitis-associated cancer remains poorly defined. Here, it is demonstrated that TGF-ß promotes the colonic inflammation and related tumorigenesis in the absence of Smad family member 4 (Smad4). Smad4 loss in intestinal epithelium aggravates colitis and colitis-associated neoplasia induced by dextran sulfate sodium (DSS) and azoxymethane/dextran sulfate sodium (AOM/DSS), leading to over-activated immune responses and increased TGF-ß1 levels. In Smad4-deficient organoids, TGF-ß1 stimulates spheroid formation and impairs intestinal stem cell proliferation and lineage specification. YAP, whose expression is directly upregulated by TGF-ß1 after Smad4 deletion, mediates the effect of TGF-ß1 by interacting with Smad2/3. Attenuation of YAP/TAZ prevents TGF-ß1-induced spheroid formation in Smad4-/- organoids and alleviates colitis and colitis-associated cancer in Smad4-deficient mice. Collectively, these results highlight an integral role of the TGF-ß/Smad4 axis in restraining intestinal inflammation and tumorigenesis and suggest TGF-ß or YAP signaling as therapeutic targets for these gastrointestinal diseases intervention.