FXR 调节肠道肿瘤干细胞增殖。
FXR Regulates Intestinal Cancer Stem Cell Proliferation.
机构信息
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead NSW 2145, Australia.
出版信息
Cell. 2019 Feb 21;176(5):1098-1112.e18. doi: 10.1016/j.cell.2019.01.036.
Abstract
Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5 cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5 cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.
摘要
肠道胆汁酸（BAs）水平升高是结直肠癌（CRC）的一个风险因素。在这里，我们表明，饮食因素（高脂肪饮食）和 WNT 信号失调（APC 突变）的汇聚改变了 BA 谱，从而驱动 Lgr5 表达（Lgr5）癌症干细胞的恶性转化，并促进腺瘤-腺癌的进展。从机制上讲，我们表明，拮抗肠道法尼醇 X 受体（FXR）功能的 BA，包括牛磺-β-鼠胆酸（T-βMCA）和脱氧胆酸（DCA），可诱导 Lgr5 细胞增殖和 DNA 损伤。相反，肠道 FXR 的选择性激活可以限制异常 Lgr5 细胞的生长并遏制 CRC 的进展。FXR 在协调肠道自我更新与 BA 水平方面的这种意外作用暗示 FXR 可能是 CRC 的一个潜在治疗靶点。
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本文引用的文献
1
A single-cell survey of the small intestinal epithelium.小肠上皮的单细胞调查。
Nature. 2017 Nov 16;551(7680):333-339. doi: 10.1038/nature24489. Epub 2017 Nov 8.
2
Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention.干细胞分裂、体细胞突变、癌症病因学与癌症预防。
Science. 2017 Mar 24;355(6331):1330-1334. doi: 10.1126/science.aaf9011.
3
Interplay between metabolic identities in the intestinal crypt supports stem cell function.肠道隐窝中的代谢身份相互作用支持干细胞功能。
Nature. 2017 Mar 16;543(7645):424-427. doi: 10.1038/nature21673. Epub 2017 Mar 8.
4
Liver Cancer Checks in When Bile Acid Clocks Out.当胆汁酸“下班”时，肝癌便“上岗”了。
Cancer Cell. 2016 Dec 12;30(6):827-828. doi: 10.1016/j.ccell.2016.11.012.
5
Bile Acid Analog Intercepts Liver Fibrosis.胆汁酸类似物阻断肝纤维化。
Cell. 2016 Aug 11;166(4):789. doi: 10.1016/j.cell.2016.08.001.
6
Colorectal cancer.结直肠癌。
Nat Rev Dis Primers. 2015 Nov 5;1:15065. doi: 10.1038/nrdp.2015.65.
7
High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.高脂饮食增强肠道祖细胞的干性和致瘤性。
Nature. 2016 Mar 3;531(7592):53-8. doi: 10.1038/nature17173.
8
Obesity and Cancer: The Oil that Feeds the Flame.肥胖与癌症：火上浇油。
Cell Metab. 2016 Jan 12;23(1):48-62. doi: 10.1016/j.cmet.2015.12.015.
9
Microbiota-induced obesity requires farnesoid X receptor.微生物群诱导的肥胖需要法尼醇X受体。
Gut. 2017 Mar;66(3):429-437. doi: 10.1136/gutjnl-2015-310283. Epub 2016 Jan 6.
10
Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells.腺瘤性息肉病 coli 的失活通过 Fxr 基因 CpG 甲基化降低小鼠结肠肿瘤和人结肠癌细胞中胆汁酸/法尼醇 X 受体的表达。
J Nutr. 2016 Feb;146(2):236-42. doi: 10.3945/jn.115.216580. Epub 2015 Nov 25.
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