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Mutations in  TGFBR2 , a component of the transforming growth factor (TGF)-β signaling pathway, occur in high-frequency microsatellite instability (MSI-H) colorectal cancer (CRC). In mouse models,  Tgfbr2  inactivation in the intestinal epithelium accelerates the development of malignant intestinal tumors in combination with disruption of the Wnt-β-catenin pathway. However, no studies have further identified the genes influenced by  TGFBR2  inactivation following disruption of the Wnt-β-catenin pathway. We previously described  CDX2P-G19Cre ; Apc   flox/flox   mice, which is stochastically null for  Apc  in the colon epithelium. In this study, we generated  CDX2P-G19Cre ; Apc   flox/flox  ; Tgfbr2   flox/flox   mice, with simultaneous loss of  Apc  and  Tgfbr2 . These mice developed tumors, including adenocarcinoma in the proximal colon. We compared gene expression profiles between tumors of the two types of mice using microarray analysis. Our results showed that the expression of the murine homolog of  GSDMC  was significantly upregulated by 9.25-fold in tumors of  CDX2P-G19Cre ; Apc   flox/flox  ; Tgfbr2   flox/flox   mice compared with those of  CDX2P-G19Cre ; Apc   flox/flox   mice. We then investigated the role of GSDMC in regulating CRC tumorigenesis. The silencing of GSDMC led to a significant reduction in the proliferation and tumorigenesis of CRC cell lines, whereas the overexpression of GSDMC enhanced cell proliferation. These results suggested that GSDMC functioned as an oncogene, promoting cell proliferation in colorectal carcinogenesis. In conclusion, combined inactivation of both Apc and Tgfbr2 in the colon epithelium of a CRC mouse model promoted development of adenocarcinoma in the proximal colon. Moreover, GSDMC was upregulated by  TGFBR2  mutation in CRC and promoted tumor cell proliferation in CRC carcinogenesis, suggesting that GSDMC may be a promising therapeutic target.

plos one

Gasdermin C Is Upregulated by Inactivation of Transforming Growth Factor β Receptor Type II in the Presence of Mutated Apc, Promoting Colorectal Cancer Proliferation