Transforming Growth Factor Beta Promotes Inflammation and Tumorigenesis in Smad4‐Deficient Intestinal Epithelium in a YAP‐Dependent Manner
Liansheng Liu, Yalong Wang, Shicheng Yu, Huidong Liu, Yehua Li, Shan Hua, Ye‐Guang Chen
Abstract
Abstract Transforming growth factor beta (TGF‐ β ), a multifunctional cytokine, plays critical roles in immune responses. However, the precise role of TGF‐ β in colitis and colitis‐associated cancer remains poorly defined. Here, it is demonstrated that TGF‐ β 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‐ β 1 levels. In Smad4 ‐deficient organoids, TGF‐ β 1 stimulates spheroid formation and impairs intestinal stem cell proliferation and lineage specification. YAP, whose expression is directly upregulated by TGF‐ β 1 after Smad4 deletion, mediates the effect of TGF‐ β 1 by interacting with Smad2/3. Attenuation of YAP/TAZ prevents TGF‐ β 1‐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‐ β /Smad4 axis in restraining intestinal inflammation and tumorigenesis and suggest TGF‐ β or YAP signaling as therapeutic targets for these gastrointestinal diseases intervention.