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结肠炎期间升高的 d-2-羟戊二酸会促使结直肠癌的发展。

Elevated d-2-hydroxyglutarate during colitis drives progression to colorectal cancer.

机构信息

Division of Gastroenterology, Department of Internal Medicine, Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX 75204.

Institute of Metabolic Disease, Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX 75204.

出版信息

Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1057-1062. doi: 10.1073/pnas.1712625115. Epub 2018 Jan 16.

DOI:10.1073/pnas.1712625115
PMID:29339485
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5798335/
Abstract

d-2-hydroxyglutarate (D2HG) is produced in the tricarboxylic acid cycle and is quickly converted to α-ketoglutarate by d-2-hydroxyglutarate dehydrogenase (D2HGDH). In a mouse model of colitis-associated colon cancer (CAC), urine level of D2HG during colitis correlates positively with subsequent polyp counts and severity of dysplasia. The i.p. injection of D2HG results in delayed recovery from colitis and severe tumorigenesis. The colonic expression of D2HGDH is decreased in ulcerative colitis (UC) patients at baseline who progress to cancer. Hypoxia-inducible factor (Hif)-1α is a key regulator of D2HGDH transcription. Our study identifies urine D2HG and tissue D2HGDH expression as biomarkers to identify patients at risk for progressing from colitis to cancer. The D2HG/D2HGDH pathway provides potential therapeutic targets for the treatment of CAC.

摘要

D-2-羟基戊二酸（D2HG）在三羧酸循环中产生，并且很快被 D-2-羟基戊二酸脱氢酶（D2HGDH）转化为α-酮戊二酸。在结肠炎相关结肠癌（CAC）的小鼠模型中，结肠炎期间尿中 D2HG 的水平与随后的息肉数量和发育异常的严重程度呈正相关。D2HG 的腹腔注射导致结肠炎的恢复延迟和严重的肿瘤发生。在基线时进展为癌症的溃疡性结肠炎（UC）患者中，结肠中 D2HGDH 的表达降低。缺氧诱导因子（Hif）-1α是 D2HGDH 转录的关键调节因子。我们的研究确定尿 D2HG 和组织 D2HGDH 表达作为生物标志物，以识别从结肠炎进展为癌症的风险患者。D2HG/D2HGDH 途径为 CAC 的治疗提供了潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/6fc48edb8f5c/pnas.1712625115fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/23a7b2a2056c/pnas.1712625115fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/23b4f4801957/pnas.1712625115fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/7554c5aac0f2/pnas.1712625115fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/ec6603ced147/pnas.1712625115fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/6fc48edb8f5c/pnas.1712625115fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/23a7b2a2056c/pnas.1712625115fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/23b4f4801957/pnas.1712625115fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/7554c5aac0f2/pnas.1712625115fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/ec6603ced147/pnas.1712625115fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5905/5798335/6fc48edb8f5c/pnas.1712625115fig05.jpg

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