Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis.
Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis.
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DOI：
10.1038/s41388-018-0492-9
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发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Wilson KT
中科院分区：
文献类型：
--
作者：
Coburn LA;Singh K;Asim M;Barry DP;Allaman MM;Al-Greene NT;Hardbower DM;Polosukhina D;Williams CS;Delgado AG;Piazuelo MB;Washington MK;Gobert AP;Wilson KT
溶质载体家族7成员2（SLC 7A 2，也称为CAT 2）是半必需氨基酸L-精氨酸（L-Arg）的诱导型转运蛋白，其已经涉及伤口修复。我们已经报道了在来自炎性肠病患者的结肠组织中SLC 7A 2表达和L-Arg可用性均降低，并且与野生型（WT）小鼠相比，缺乏Slc 7a 2的小鼠在暴露于葡聚糖硫酸钠（DSS）时表现出更严重的病程。在这里，我们提出的证据表明，SLC 7A 2在结肠炎相关致癌作用（CAC）的氧化偶氮甲烷（AOM）-DSS模型中调节结肠肿瘤发生中起作用。SLC 7A 2主要定位于WT小鼠的结肠上皮细胞。利用AOM-DSS模型，与WT小鼠相比，Slc 7a 2-/-小鼠具有显著增加的肿瘤数量、负荷和高度发育不良的风险。与来自WT小鼠的肿瘤相比，来自Slc 7a 2-/-小鼠的肿瘤表现出促炎细胞因子/趋化因子IL-1β、CXCL 1、CXCL 5、IL-3、CXCL 2、CCL 3和CCL 4的水平显著增加，但IL-4、CXCL 9和CXCL 10的水平降低。这伴随着Slc 7a 2缺陷小鼠中促肿瘤发生M2巨噬细胞活化的转变，其标志是结肠CD 11b +F4/80+ Arg 1+细胞增加，而CD 11b +F4/80+ NOS 2+细胞没有变化。流式细胞术和免疫荧光显微镜。在来自Slc 7a 2-/-小鼠的骨髓来源的巨噬细胞中证实了向M2巨噬细胞活化的转变。在Slc 7a 2-/-和WT小鼠之间的骨髓嵌合体中，受体基因型驱动CAC表型，表明上皮细胞SLC 7A 2在消除肿瘤风险中的重要性。这些数据表明，SLC 7A 2在慢性结肠炎背景下对CAC的保护中具有重要作用，并表明炎症性肠病（IBD）中SLC 7A 2的降低可能导致CAC风险。通过补充L-Arg和/或增加L-Arg摄取来增强L-Arg可用性的策略可能代表IBD的治疗方法，以降低结直肠癌的长期风险。
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.
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影响因子：
9.8
作者：
CASTILLO, L;AJAMI, A;YOUNG, VR
通讯作者：
YOUNG, VR
影响因子：
3.5
作者：
Hardbower, Dana M.;Asim, Mohammad;Murray-Stewart, Tracy;Casero, Robert A., Jr.;Verriere, Thomas;Lewis, Nuruddeen D.;Chaturvedi, Rupesh;Piazuelo, M. Blanca;Wilson, Keith T.
通讯作者：
Wilson, Keith T.
影响因子：
5.5
作者：
Martín, L;Comalada, M;Bertran, J
通讯作者：
Bertran, J
影响因子：
64.8
作者：
Khor, Bernard;Gardet, Agnes;Xavier, Ramnik J.
通讯作者：
Xavier, Ramnik J.
DOI：
10.1084/jem.182.1.155
发表时间：
1995-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Angiolillo AL;Sgadari C;Taub DD;Liao F;Farber JM;Maheshwari S;Kleinman HK;Reaman GH;Tosato G
通讯作者：
Tosato G