Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer

被引：61

作者：

Means, Anna L. ^{[1
,2
,5
]}

Freeman, Tanner J. ^{[1
,2
,9
]}

Zhu, Jing ^{[1
]}

Woodbury, Luke G. ^{[1
]}

Marincola-Smith, Paula ^{[1
]}

Wu, Chao ^{[6
]}

Meyer, Anne R. ^{[1
,2
]}

Weaver, Connie J. ^{[1
]}

Padmanabhan, Chandrasekhar ^{[1
]}

An, Hanbing ^{[1
]}

Zi, Jinghuan ^{[1
]}

Wessinger, Bronson C. ^{[1
]}

Chaturvedi, Rupesh ^{[3
,10
]}

Brown, Tasia D. ^{[1
,11
]}

Deane, Natasha G. ^{[1
]}

Coffey, Robert J. ^{[3
,5
,8
]}

Wilson, Keith T. ^{[3
,4
,5
,8
]}

Smith, J. Joshua ^{[6
]}

Sawyers, Charles L. ^{[6
,7
]}

Goldenring, James R. ^{[1
,2
,5
,8
]}

Novitskiy, Sergey V. ^{[3
]}

Washington, M. Kay ^{[4
,5
]}

Shi, Chanjuan ^{[4
,5
]}

Beauchamp, R. Daniel ^{[1
,2
,5
]}

机构：

[1] Vanderbilt Univ, Dept Surg, Med Ctr, Nashville, TN 37240 USA

[2] Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN USA

[3] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA

[4] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA

[5] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN USA

[6] Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[8] Vet Affairs Tennessee Valley Healthcare Syst, Nashville, TN USA

[9] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA

[10] Jawaharlal Nehru Univ, New Delhi, India

[11] ICON PLC, Nashville, TN USA

来源：

CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY | 2018年 / 6卷 / 03期

基金：

美国国家卫生研究院;

关键词：

TGF beta; Colitis-Associated Carcinoma; Tumor Necrosis Factor; GROWTH-FACTOR-BETA; DIFFERENTIAL EXPRESSION ANALYSIS; ULCERATIVE-COLITIS; TGF-BETA; BOWEL-DISEASE; COLON-CANCER; SMALL-INTESTINE; IMMUNE CELLS; T-CELLS; TUMORIGENESIS;

D O I：

10.1016/j.jcmgh.2018.05.006

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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 beta (TGF beta) 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 TGF beta 1 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, TGF beta signaling inhibited the epithelial inflammatory response to proinflammatory cytokines. CONCLUSIONS: TGF beta 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.

引用

页码：257 / 276

页数：20

共 62 条

[1]

Four Jointed Box 1 Promotes Angiogenesis and Is Associated with Poor Patient Survival in Colorectal Carcinoma [J].