Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis

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 CD11bF4/80ARG1 cells with no alteration in CD11bF4/80NOS2 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.

Transcriptional and Metabolomic Analysis of L-Arginine/Nitric Oxide Pathway in Inflammatory Bowel Disease and Its Association with Local Inflammatory and Angiogenic Response: Preliminary Findings

“…Unlike in other studies [21], active CD here was associated with diminished systemic arginine concentrations and, like in other studies [24], no difference in the case of UC was observed. Knockout studies have shown that arginine transporters, and thus arginine, are necessary to reduce mucosal inflammation and the incidence of colitis-associated tumorigenesis [20]. Accordingly, dietary arginine is claimed to be beneficial in animal models of colitis.…”

“…Its deprivation is viewed as a way to starve the arginine auxotrophic tumors [11,18]. In IBD, on the contrary, arginine supplementation is advocated both for chemoprevention of colitis-associated carcinogenesis and for reduction of colonic inflammation [19,20].…”

Apoptotic caspases inhibit abscopal responses to radiation and identify a new prognostic biomarker for breast cancer patients

“…The molecular mechanisms whereby CLIC6 expression may positively impact on survival remain obscure. Conversely, SLC7A2 (which was enriched in patients with good prognosis) is known for its anti-inflammatory effects, 50 at least in part linked to its key role in the immunosuppressive activity of myeloid-derived suppressor cells. 51 These observations lend further support to the notion that chronic, indolent Figure 6.…”

Progressive shifts in the gut microbiome reflect prediabetes and diabetes development in a treatment-naive Mexican cohort

“…Loss of Blautia has also been associated with an inflamed gut in Crohn's disease and other clinical conditions 36,37 . Additionally, alterations in solute carrier expression as present in the Mexican population 12 have been observed in the development of irritable bowel disease and have been linked to inflammation 38,39 .…”