期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 125, 期 7, 页码 2646-2660出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI76099
关键词
-
资金
- VA [1I01BX001426-01A1, 548419] Funding Source: Federal RePORTER
- NCATS NIH HHS [2 UL1 TR000445-06, UL1 TR000445] Funding Source: Medline
- NCCIH NIH HHS [R01 AT004821, R01AT004821, R01AT004821-S1] Funding Source: Medline
- NCI NIH HHS [F30 CA165726, P50 CA095103, R01 CA190612, 1F31CA167920, P01 CA028842, T32CA009592-26, P01CA116087, P01CA028842, P30CA068485, P50CA095103, F31 CA167920, T32 CA009592, P30 CA068485, P01 CA116087, 1F30CA165726, R01 CA142826] Funding Source: Medline
- NCRR NIH HHS [UL1 RR024975-01, UL1 RR024975] Funding Source: Medline
- NIAID NIH HHS [U19 AI116497] Funding Source: Medline
- NIDDK NIH HHS [K08 DK080221, 1F30DK103498, F30 DK103498, R01 DK099204, 1F30DK096718, P30 DK058404, DK080221, R01 DK053620, F30 DK096718, R01DK053620, P30DK058404] Funding Source: Medline
- NIEHS NIH HHS [R37 ES002497] Funding Source: Medline
- NIGMS NIH HHS [T32GM07347, T32 GM07347, R25 GM062459, T32 GM007347] Funding Source: Medline
- NIH HHS [S10 OD021630] Funding Source: Medline
- BLRD VA [I01 BX001426, I01 BX001453] Funding Source: Medline
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据