Abstract
Solute carrier family 7 member 2 (SLC7A2, also known as CAT2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in wound repair. We have reported that both SLC7A2 expression and L-Arg availability are decreased in colonic tissues from inflammatory bowel disease patients and that mice lacking Slc7a2 exhibit a more severe disease course when exposed to dextran sulfate sodium (DSS) compared to wild-type (WT) mice. Here, we present evidence that SLC7A2 plays a role in modulating colon tumorigenesis in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis (CAC). SLC7A2 was localized predominantly to colonic epithelial cells in WT mice. Utilizing the AOM-DSS model, Slc7a2–/– mice had significantly increased tumor number, burden, and risk of high-grade dysplasia vs. WT mice. Tumors from Slc7a2–/– mice exhibited significantly increased levels of the proinflammatory cytokines/chemokines IL-1β, CXCL1, CXCL5, IL-3, CXCL2, CCL3, and CCL4, but decreased levels of IL-4, CXCL9, and CXCL10 compared to tumors from WT mice. This was accompanied by a shift toward pro-tumorigenic M2 macrophage activation in Slc7a2-deficient mice, as marked by increased colonic CD11b+F4/80+ARG1+ cells with no alteration in CD11b+F4/80+NOS2+ cells by flow cytometry and immunofluorescence microscopy. The shift toward M2 macrophage activation was confirmed in bone marrow-derived macrophages from Slc7a2–/– mice. In bone marrow chimeras between Slc7a2–/– and WT mice, the recipient genotype drove the CAC phenotype, suggesting the importance of epithelial SLC7A2 in abrogating neoplastic risk. These data reveal that SLC7A2 has a significant role in the protection from CAC in the setting of chronic colitis, and suggest that the decreased SLC7A2 in inflammatory bowel disease (IBD) may contribute to CAC risk. Strategies to enhance L-Arg availability by supplementing L-Arg and/or increasing L-Arg uptake could represent a therapeutic approach in IBD to reduce the substantial long-term risk of colorectal carcinoma.
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Acknowledgements
This work was funded by the National Institutes of Health (NIH) grants R01AT004821, 3R01AT004821-02S1, R01DK053620, R01CA190612, P01CA116087, and P01CA028842 (to KTW), Veterans Affairs Merit Review grant I01BX001453 (to KTW), the Thomas F. Frist Sr. Endowment (to KTW), and the Vanderbilt Center for Mucosal Inflammation and Cancer (to KTW). LAC was supported by the NIH training grant 5T32DK007673, a Vanderbilt Physician Scientist Development Award, and a Veterans Affairs Career Development Award 1IK2BX002126. DMH was supported by T32GM008554 and F31DK10715. Additional support was provided by the NIH grant P30DK058404 (Vanderbilt Digestive Disease Research Center). Whole slide imaging and quantification were performed in the Digital Histology Shared Resource at the Vanderbilt University Medical Center (http://www.mc.vanderbilt.edu/dhsr).
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Coburn, L.A., Singh, K., Asim, M. et al. Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis. Oncogene 38, 1067–1079 (2019). https://doi.org/10.1038/s41388-018-0492-9
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DOI: https://doi.org/10.1038/s41388-018-0492-9
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