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MTG16 is a tumor suppressor in colitis-associated carcinoma
Elizabeth M. McDonough, … , Keith T. Wilson, Christopher S. Williams
Elizabeth M. McDonough, … , Keith T. Wilson, Christopher S. Williams
Published August 17, 2017
Citation Information: JCI Insight. 2017;2(16):e78210. https://doi.org/10.1172/jci.insight.78210.
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Research Article Gastroenterology Genetics Inflammation Oncology

MTG16 is a tumor suppressor in colitis-associated carcinoma

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Abstract

MTG16 is a member of the myeloid translocation gene (MTG) family of transcriptional corepressors. While MTGs were originally identified in chromosomal translocations in acute myeloid leukemia, recent studies have uncovered a role in intestinal biology. For example, Mtg16–/– mice have increased intestinal proliferation and are more sensitive to intestinal injury in colitis models. MTG16 is also underexpressed in patients with moderate/severe ulcerative colitis. Based on these findings, we postulated that MTG16 might protect against colitis-associated carcinogenesis. MTG16 was downregulated at the protein and RNA levels in patients with inflammatory bowel disease and in those with colitis-associated carcinoma. Mtg16–/– mice subjected to inflammatory carcinogenesis modeling exhibited worse colitis and increased tumor multiplicity and size. Loss of MTG16 also increased severity of dysplasia, apoptosis, proliferation, DNA damage, and WNT signaling. Moreover, transplantation of WT marrow into Mtg16–/– mice failed to rescue the Mtg16–/– protumorigenic phenotypes, indicating an epithelium-specific role for MTG16. While MTG dysfunction is widely appreciated in hematopoietic malignancies, the role of this gene family in epithelial homeostasis, and in colon cancer, was unrealized. This report identifies MTG16 as an important modulator of colitis and tumor development in inflammatory carcinogenesis.

Authors

Elizabeth M. McDonough, Caitlyn W. Barrett, Bobak Parang, Mukul K. Mittal, J. Joshua Smith, Amber M. Bradley, Yash A. Choksi, Lori A. Coburn, Sarah P. Short, Joshua J. Thompson, Baolin Zhang, Shenika V. Poindexter, Melissa A. Fischer, Xi Chen, Jiang Li, Frank L. Revetta, Rishi Naik, M. Kay Washington, Michael J. Rosen, Scott W. Hiebert, Keith T. Wilson, Christopher S. Williams

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Figure 6

MTG16 represses Wnt signaling.

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MTG16 represses Wnt signaling.
(A) β-Catenin expression by immunohistoch...
(A) β-Catenin expression by immunohistochemistry. Representative images from WT and Mtg16–/– tumors stained for β-catenin (left, images ×10 magnification) and quantification of β-catenin staining index (right, percentage of tumors with nuclear β-catenin multiplied by expression intensity (WT = 13, Mtg16–/– = 14), Student’s t test. (B) MTG16-repressed transcription of TOPFLASH reporter in NIH3T3 cells transfected with increasing amounts of Mtg16, as shown (triplicates and repeated twice). (C) Increased frequency of X-gal–positive crypts in Mtg16–/– mice (left, images ×20 magnification) and quantification of percentage of X-gal–positive crypts (right, WT = 12, Mtg16–/– = 4 mice), Student’s t test. (D) Coimmunoprecipitation of MTG colorectal cancer–associated (CRC-associated) mutants and TCF4 and (E) TOPFLASH assay with individual MTG8 mutants (n = 12/category). One-way ANOVA and Newman-Keuls post-test, **P < 0.01, ***P < 0.001. RLU, relative light units; IP, immunoprecipitation; WCL, whole-cell lysate.

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