Abstract
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;Apcflox/flox mice, which is stochastically null for Apc in the colon epithelium. In this study, we generated CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/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;Apcflox/flox;Tgfbr2flox/flox mice compared with those of CDX2P-G19Cre;Apcflox/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.
Highlights
The classic paradigm of colorectal cancer (CRC) formation follows the adenoma-carcinoma sequence, in which CRC begins as an adenoma [1]
In clinical studies examining how mutations in the TGFBR2 gene affect the development of microsatellite instability (MSI)-H CRCs, tumors with TGFBR2 mutations were shown to be more frequently located in the right-sided colon, usually had a poor degree of differentiation, tended to appear more frequently as Dukes B stage, and had worse prognoses than those without mutations, indicating that TGFBR2 mutations contributed to tumor progression through the MSI pathway [14]
The proximal colons of CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice exhibited multiple polypoid lesions, and histological analysis showed that these tumors were well-differentiated adenocarcinomas, similar to those observed in CDX2P-G19Cre;Apcflox/flox mice (Fig 1C–1F)
Summary
The classic paradigm of colorectal cancer (CRC) formation follows the adenoma-carcinoma sequence, in which CRC begins as an adenoma [1]. In CRC, the components of the TGF-β signaling pathway, TGFBR2 and Smad, are frequently mutated [7, 8]. TGFBR2 mutations occur in the latter phase of CRC carcinogenesis when adenoma transitions to carcinoma in approximately 60–90% of high-frequency microsatellite instability (MSI-H) CRCs [9,10,11,12,13]. In clinical studies examining how mutations in the TGFBR2 gene affect the development of MSI-H CRCs, tumors with TGFBR2 mutations were shown to be more frequently located in the right-sided colon, usually had a poor degree of differentiation, tended to appear more frequently as Dukes B stage, and had worse prognoses than those without mutations, indicating that TGFBR2 mutations contributed to tumor progression through the MSI pathway [14]. The association between prognosis and TGFBR2 mutations in MSI-H CRCs is unclear
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