Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis
| العنوان: | Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis |
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| المؤلفون: | Margaret M. Allaman, Keith T. Wilson, Mohammad Asim, Christopher S. Williams, Alberto G. Delgado, Lori A. Coburn, Dina Polosukhina, Dana M. Hardbower, Daniel P. Barry, Kshipra Singh, M. Kay Washington, Alain P. Gobert, Nicole T. Al-Greene, M. Blanca Piazuelo |
| المصدر: | Oncogene |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | SLC7A2, 0301 basic medicine, Cancer Research, Chemokine, Azoxymethane, Inflammation, Biology, Inflammatory bowel disease, Article, Proinflammatory cytokine, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Line, Tumor, Genetics, medicine, Animals, M2 macrophages, Molecular Biology, Mice, Knockout, Inflammatory Bowel Diseases, M2 Macrophage, medicine.disease, Neoplasm Proteins, 3. Good health, CXCL1, tumorigenesis, CXCL2, Cell Transformation, Neoplastic, 030104 developmental biology, colon cancer, chemistry, 030220 oncology & carcinogenesis, Colonic Neoplasms, Cancer research, biology.protein, Amino Acid Transport Systems, Basic, medicine.symptom |
| الوصف: | 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 versus 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. |
| تدمد: | 1476-5594 0950-9232 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e3dc506ae7bf74d0f719d18a5c120454 https://doi.org/10.1038/s41388-018-0492-9 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e3dc506ae7bf74d0f719d18a5c120454 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14765594 09509232 |
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