Abstract #2349: Mtgr1 is a tumor modifier in inflammatory carcinogenesis in the colon

Abstract

MTGR1 (Myeloid Translocation Gene, Related-1) is a member of a gene family originally identified as targets of chromosomal translocation in acute myeloid leukemia (AML). Recent work from our laboratory has shown that MTGR1 plays a role in intestinal differentiation, wound healing, and inflammation and that this, in part, occurs via MTG-mediated repression of TCF4. Given the role of MTG family members in hematopoietic malignancy, the ability of MTGR1 to modulate WNT signaling, and the fact that loss of MTGR1 results in sensitization to gut injury, we hypothesized that MTGR1 may influence tumorigenesis arising in an inflammatory background. The AOM/DSS model is a robust model for interrogating modifiers of intestinal carcinogenesis. 19 C57bl6 Mtgr1^-/- and 22 WT mice were injected with 12 mg/kg AOM followed 5 days later with the first of four cycles of 4 days of 3% DSS ad lib, with each cycle separated by 16 days of recovery and animals sacrificed 1 month after the last cycle of DSS treatment. Two hours prior to sacrifice 16.5 ug/kg of BrdU was injected IP. At necropsy colons were isolated and tumor burden, size and distribution scored. IHC for BrdU, \#946;-catenin, COX-2, and CD3 was performed. RNA was isolated and expression array analysis performed using the Affymetrix Mouse Gene 1.0 platform. Mtgr1^-/- mice were protected from tumorigenesis with decreased tumor number (1.7 vs 7.5 polyps per colon, p<0.001), decreased multiplicity, and reduced surface area per lesion (27 vs 82 mm², p=0.01). Mtgr1^-/- tumors had similar proliferation, but significantly higher intra-tumoral apoptosis rates when compared to WT tumors, potentially explaining the difference in size and number (32 vs 13 TUNEL (+) cells/HPF, p<0.001). Panther analysis of mRNA expression array data from Mtgr1^-/- vs WT tumor samples revealed significant upregulation of inflammatory networks and a decrease in WNT signaling networks in the Mtgr1^-/- tumors (p<0.001). In support of these observations, \#946;-catenin IHC showed decreased nuclear \#946;-catenin and CD3⁺ IHC revealed increased T-cell infiltrate in Mtgr1^-/- tumors (49.4 vs 13.6 CD3⁺ cells/hpf, p<0.001). MTGR1-specific TaqMan analysis of Origene TissueScan Cancer surveys revealed a trend towards increased expression in breast, colon, prostate and lung carcinoma. Surveying of matched colorectal cancer and normal tissue revealed heterogeneity in expression with 68% of samples showing increased Mtgr1 expression. These studies provide the first evidence that MTGR1 may function as a tumor promoter in intestinal carcinogenesis.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2349.