Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage
Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage
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DOI：
10.1172/jci76099
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发表时间：
2015-07-01
影响因子：
15.9
通讯作者：
Williams, Christopher S.
中科院分区：
文献类型：
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作者：
Barrett, Caitlyn W.;Reddy, Vishruth K.;Williams, Christopher S.
炎症性肠病患者由于氧化应激增强而患结肠癌的风险增加。这些患者由于营养缺乏也损害了抗氧化防御。微量营养素硒是硒蛋白产生所必需的，并通过硒蛋白P（SEPP 1）从肝脏转运到靶组织。靶组织也产生SEPP 1，其被认为具有内源性抗氧化功能。在这里，我们已经表明，小鼠Sepp 1单倍不足或突变，破坏硒转运或SEPP 1的酶结构域表现出增加结肠炎相关的致癌作用，作为增加基因组不稳定性和促进促肿瘤微环境的结果。SEPP 1功能的降低显著增加了M2极化的巨噬细胞，表明SEPP 1在巨噬细胞极化和免疫功能中的作用。此外，与部分缺失相比，SEPP 1的完全缺失显著降低了肿瘤负荷，部分原因是细胞凋亡增加。使用肠道类器官培养物，我们发现，与野生型动物相比，Sepp 1-null培养物显示出增加的干细胞特征，这些特征与增加的ROS产生、DNA损伤、增殖、细胞存活率降低以及响应H2 O2介导的氧化应激的WNT信号转导的调节相结合。总之，这些数据表明，SEPP 1通过影响基因组稳定性、炎症微环境和上皮干细胞功能来影响炎症性肿瘤发生。
Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.