Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Oncogene. 2019 Feb;38(7):1067-1079. doi: 10.1038/s41388-018-0492-9. Epub 2018 Sep 10.
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.
溶质载体家族 7 成员 2（SLC7A2，也称为 CAT2）是一种半必需氨基酸 L-精氨酸（L-Arg）的诱导型转运蛋白，它与伤口修复有关。我们已经报道，炎症性肠病患者的结肠组织中 SLC7A2 的表达和 L-Arg 的可用性都降低了，与野生型（WT）小鼠相比，缺乏 Slc7a2 的小鼠在暴露于葡聚糖硫酸钠（DSS）时表现出更严重的疾病过程。在这里，我们提供的证据表明，SLC7A2 在调节结肠炎相关癌变（CAC）的氧化偶氮甲烷（AOM）-DSS 模型中的结肠肿瘤发生中发挥作用。SLC7A2 在 WT 小鼠的结肠上皮细胞中主要定位于。利用 AOM-DSS 模型，Slc7a2 小鼠的肿瘤数量、负担和高级别发育不良的风险显著高于 WT 小鼠。与 WT 小鼠的肿瘤相比，Slc7a2 小鼠的肿瘤显示出明显增加的促炎细胞因子/趋化因子 IL-1β、CXCL1、CXCL5、IL-3、CXCL2、CCL3 和 CCL4 的水平，但 IL-4、CXCL9 和 CXCL10 的水平降低。这伴随着 Slc7a2 缺陷型小鼠向促肿瘤 M2 巨噬细胞激活的转变，这一点通过流式细胞术和免疫荧光显微镜观察到结肠 CD11bF4/80ARG1 细胞的增加而没有 CD11bF4/80NOS2 细胞的改变来标记。在 Slc7a2 小鼠的骨髓来源巨噬细胞中证实了向 M2 巨噬细胞激活的转变。在 Slc7a2 和 WT 小鼠之间的骨髓嵌合体中，受者基因型驱动 CAC 表型，这表明上皮 SLC7A2 在消除肿瘤风险方面的重要性。这些数据表明，SLC7A2 在慢性结肠炎的 CAC 保护中具有重要作用，并表明炎症性肠病（IBD）中 SLC7A2 的减少可能导致 CAC 风险增加。通过补充 L-Arg 和/或增加 L-Arg 摄取来增加 L-Arg 可用性的策略可能代表 IBD 中的一种治疗方法，以降低结直肠癌的长期风险。
