Epithelial SMAD4 deletion up-regulates inflammation and promotes inflammation-associated cancer Journal Article
| Authors: | Means, A. L.; Freeman, T. J.; Zhu, J.; Woodbury, L. G.; Marincola-Smith, P.; Wu, C.; Meyer, A. R.; Weaver, C. J.; Padmanabhan, C.; An, H.; Zi, J.; Wessinger, B. C.; Chaturvedi, R.; Brown, T. D.; Deane, N. G.; Coffey, R. J.; Wilson, K. T.; Smith, J. J.; Sawyers, C. L.; Goldenring, J. R.; Novitskiy, S. V.; Washington, M. K.; Shi, C.; Beauchamp, R. D. |
| Article Title: | Epithelial SMAD4 deletion up-regulates inflammation and promotes inflammation-associated cancer |
| Abstract: | Background & Aims: Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells. Methods: The Smad4 gene was deleted specifically in adult murine intestinal epithelium. Colitis was induced by 3 rounds of dextran sodium sulfate in drinking water, after which mice were observed for up to 3 months. Nontransformed mouse colonocyte cell lines and colonoid cultures and human colorectal cancer cell lines were analyzed for responses to TGFβ1 and bone morphogenetic protein 2. Results: Dextran sodium sulfate treatment was sufficient to drive carcinogenesis in mice lacking colonic Smad4 expression, with resulting tumors bearing striking resemblance to human colitis–associated carcinoma. Loss of SMAD4 protein was observed in 48% of human colitis–associated carcinoma samples as compared with 19% of sporadic colorectal carcinomas. Loss of Smad4 increased the expression of inflammatory mediators within nontransformed mouse colon epithelial cells in vivo. In vitro analysis of mouse and human colonic epithelial cell lines and organoids indicated that much of this regulation was cell autonomous. Furthermore, TGFβ signaling inhibited the epithelial inflammatory response to proinflammatory cytokines. Conclusions: TGFβ suppresses the expression of proinflammatory genes in the colon epithelium, and loss of its downstream mediator, SMAD4, is sufficient to initiate inflammation-driven colon cancer. Transcript profiling: GSE100082. © 2018 The Authors |
| Keywords: | immunohistochemistry; controlled study; human tissue; human cell; nonhuman; mouse; allele; disease association; dendritic cell; transforming growth factor beta; protein depletion; interleukin 1beta; animal experiment; animal model; cell differentiation; uvomorulin; carcinogenesis; colorectal carcinoma; neutrophil; upregulation; bone morphogenetic protein 2; tumor growth; point mutation; colon carcinoma; macrophage; stroma cell; lymphocyte; cre recombinase; chronic inflammation; tumor necrosis factor; rna sequence; interleukin 1; vimentin; interleukin 18; colon mucosa; smad4 protein; tgfΒ; epithelial derived neutrophil activating factor 78; intestine epithelium; macrophage inflammatory protein 3alpha; human; priority journal; article; colon epithelium; receptor type tyrosine protein phosphatase c; colitis-associated carcinoma; interleukin 18 receptor beta; interleukin 34; colitis associated carcinoma; dextran sulfate sodium-induced colitis; yamc cell line |
| Journal Title: | Cellular and Molecular Gastroenterology and Hepatology |
| Volume: | 6 |
| Issue: | 3 |
| ISSN: | 2352-345X |
| Publisher: | Elsevier Inc. |
| Date Published: | 2018-01-01 |
| Start Page: | 257 |
| End Page: | 276 |
| Language: | English |
| DOI: | 10.1016/j.jcmgh.2018.05.006 |
| PROVIDER: | scopus |
| PMCID: | PMC6083016 |
| PUBMED: | 30109253 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 September 2018 -- Source: Scopus |
