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MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model.

ABSTRACT: Myeloid Translocation Gene, Related-1 (MTGR1) CBFA2T2 is a member of the Myeloid Translocation Gene (MTG) family of transcriptional corepressors. The remaining two family members, MTG8 (RUNX1T1) and MTG16 (CBFA2T3) are identified as targets of chromosomal translocations in acute myeloid leukemia (AML). Mtgr1(-/-) mice have defects in intestinal lineage allocation and wound healing. Moreover, these mice show signs of impaired intestinal stem cell function. Based on these phenotypes, we hypothesized that MTGR1 may influence tumorigenesis arising in an inflammatory background. We report that Mtgr1(-/-) mice were protected from tumorigenesis when injected with azoxymethane (AOM) and then subjected to repeated cycles of dextran sodium sulfate (DSS). Tumor cell proliferation was comparable, but Mtgr1(-/-) tumors had significantly higher apoptosis rates. These phenotypes were dependent on epithelial injury, the resultant inflammation, or a combination of both as there was no difference in aberrant crypt foci (ACF) or tumor burden when animals were treated with AOM as the sole agent. Gene expression analysis indicated that Mtgr1(-/-) tumors had significant upregulation of inflammatory networks, and immunohistochemistry (IHC) for immune cell subsets revealed a marked multilineage increase in infiltrates, consisting predominately of CD3(+) and natural killer T (NKT) cells as well as macrophages. Transplantation of wild type (WT) bone marrow into Mtgr1(-/-) mice, and the reciprocal transplant, did not alter the phenotype, ruling out an MTGR1 hematopoietic cell-autonomous mechanism. Our findings indicate that MTGR1 is required for efficient inflammatory carcinogenesis in this model, and implicate its dysfunction in colitis-associated carcinoma. This represents the first report functionally linking MTGR1 to intestinal tumorigenesis.

SUBMITTER: Barrett CW

PROVIDER: S-EPMC3150168 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model.

Barrett Caitlyn W CW Fingleton Barbara B Williams Amanda A Ning Wei W Fischer Melissa A MA Washington Mary K MK Chaturvedi Rupesh R Wilson Keith T KT Hiebert Scott W SW Williams Christopher S CS

Cancer research 20110208 4

Myeloid Translocation Gene, Related-1 (MTGR1) CBFA2T2 is a member of the Myeloid Translocation Gene (MTG) family of transcriptional corepressors. The remaining two family members, MTG8 (RUNX1T1) and MTG16 (CBFA2T3) are identified as targets of chromosomal translocations in acute myeloid leukemia (AML). Mtgr1(-/-) mice have defects in intestinal lineage allocation and wound healing. Moreover, these mice show signs of impaired intestinal stem cell function. Based on these phenotypes, we hypothesiz ...[more]

PMID: 21303973

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Project description:IntroductionAngiogenin-1 (Ang1) and angiogenin-4 (Ang4) are 14-kDa ribonucleases with potent angiogenic and antimicrobial properties. The role of Ang1 and Ang4 in chronic colitis and colitis-associated cancer has not been previously studied.MethodsWild-type (WT) and angiogenin-1 knock-out (Ang1-KO) C57BL/6 mice were given azoxymethane, a colon carcinogen, 2 days in advance of three cycles of 3.5% dextran sodium sulfate (DSS). Disease activity index (DAI) was recorded, a colonoscopy was performed after each DSS treatment, and mice were euthanized (colitis, recovery, cancer) with tissue evaluated by histopathology. Ang1, Ang4, TNF-α, Il-1F062, IL-6, IL-10, IL-23, IL-33 mRNA levels were analyzed by RT-PCR.ResultsAng1-KO mice exhibited more severe colitis compared to WT mice during both the acute (P<0.05) and recovery (P<0.05) phases of each DSS cycle. Consistent with these results, colonic TNF-α, IL1-β, IL-6, IL-10, and IL-33 mRNA levels were significantly upregulated in Ang1-KO mice (P<0.05). While Ang4 increased to similar levels in both WT and Ang1-KO mice during colitis and recovery phases, WT mice were distinguished by a significant upregulation of Ang1. Interestingly, despite the reduced colitis, WT mice developed significantly more tumors compared to Ang1-KO mice (P<0.05). 134 tumors formed in WT mice (4.6 tumors/mouse) while only 46 tumors formed (1.5 tumors/mice) in Ang1-KO mice, which were also characterized by a 34-fold decrease in Ang4 compared to WT mice and the complete absence of Ang1.ConclusionsIn a mouse model of colitis-associated cancer, Ang1-KO mice develop more severe colitis, but fewer tumors compared to WT mice. Ang1 levels correlate with the severity of colitis and the development of colitis-associated cancer, while Ang4 was upregulated during both colitis and cancer. Ang1 and Ang4 play important regulatory roles in the response to chronic colitis and the development of colitis-associated cancer and may serve as novel therapeutic targets.

Dataset Information

MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model.

Publications

MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model.

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