Gasdermin C is upregulated by inactivation of transforming growth factor β receptor type II in the presence of mutated Apc, promoting colorectal cancer proliferation

Masashi Miguchi, Takao Hinoi, Manabu Shimomura, Tomohiro Adachi, Yasufumi Saito, Hiroaki Niitsu, Masatoshi Kochi, Haruki Sada, Yusuke Sotomaru, Tsuneo Ikenoue, Kunitoshi Shigeyasu, Kohji Tanakaya, Yasuhiko Kitadai, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, Hideki Ohdan

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21 Citations (Scopus)

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.

Original languageEnglish
Article numbere0166422
JournalPloS one
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Miguchi, M., Hinoi, T., Shimomura, M., Adachi, T., Saito, Y., Niitsu, H., Kochi, M., Sada, H., Sotomaru, Y., Ikenoue, T., Shigeyasu, K., Tanakaya, K., Kitadai, Y., Sentani, K., Oue, N., Yasui, W., & Ohdan, H. (2016). Gasdermin C is upregulated by inactivation of transforming growth factor β receptor type II in the presence of mutated Apc, promoting colorectal cancer proliferation. PloS one, 11(11), [e0166422]. https://doi.org/10.1371/journal.pone.0166422