Gasdermin C Is Upregulated by Inactivation of Transforming Growth Factor β Receptor Type II in the Presence of Mutated Apc, Promoting Colorectal Cancer Proliferation.
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.
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Masashi
M
Miguchi
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.|Department of Surgery, Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan.
Takao
T
Hinoi
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Manabu
M
Shimomura
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Tomohiro
T
Adachi
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Yasufumi
Y
Saito
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Hiroaki
H
Niitsu
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Masatoshi
M
Kochi
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Haruki
H
Sada
Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.
Yusuke
Y
Sotomaru
Division of Clinical Genome Research, the Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Tsuneo
T
Ikenoue
Department of Surgery, National Hospital Organization Iwakuni Clinical Center, Yamaguchi, Japan.
Kunitoshi
K
Shigeyasu
Department of Surgery, National Hospital Organization Iwakuni Clinical Center, Yamaguchi, Japan.
Kohji
K
Tanakaya
Departments of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.|Department of Health Science, Program in Human Culture and Science, Prefectural University of Hiroshima, Hiroshima, Japan.
Yasuhiko
Y
Kitadai
Department of Molecular Pathology, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Kazuhiro
K
Sentani
Department of Molecular Pathology, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Naohide
N
Oue
Department of Molecular Pathology, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Wataru
W
Yasui
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Hideki
H
Ohdan
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000071616:CDX2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000094524:Gasdermins
D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; D000071616:CDX2 Transcription Factor; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C425469:GSDMC protein, human; D000094524:Gasdermins; C000613192:adenomatous polyposis coli protein, mouse