结直肠癌驱动基因新发现
创作:吴芹 审核:Lexi 2019年09月23日
  • ZEB1在溃疡性结肠炎(UC)患者上皮细胞和结肠炎小鼠模型中上调,其表达促进肠道炎症和炎性结直肠癌发生;
  • 与野生型小鼠相比,ZEB1缺陷小鼠在结肠炎模型中表现出较低炎症,在CRC模型中表现为DNA损伤(8-oxo-dG)及肿瘤减少、DNA修复糖基酶MPG表达更高;
  • ZEB1表达可介导氧化应激和炎症细胞因子诱导的CRC细胞DNA碱基损伤;
  • ZEB1直接结合MPG启动子抑制其表达;
  • ZEB1可作为结肠炎和UC的重要驱动因素。
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Lexi
慢性炎症是结直肠癌风险因素之一,发炎的基质释放的活性氧(ROS)导致上皮细胞DNA损伤。近期发表在Gut上的最新研究揭示了ZEB1对溃疡性结肠炎与炎性结直肠癌的促进作用,其与DNA损伤及DNA修复糖基酶MPG具有紧密联系。
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Gut [IF:19.819]

ZEB1 promotes inflammation and progression towards inflammation-driven carcinoma through repression of the DNA repair glycosylase MPG in epithelial cells

ZEB1通过抑制上皮细胞DNA修复糖基酶MPG,促进炎症和炎性肿瘤的进展

10.1136/gutjnl-2018-317294

2019-07-31, Article

Abstract & Authors:展开

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Objective: Chronic inflammation is a risk factor in colorectal cancer (CRC) and reactive oxygen species (ROS) released by the inflamed stroma elicit DNA damage in epithelial cells. We sought to identify new drivers of ulcerative colitis (UC) and inflammatory CRC.
Design : The study uses samples from patients with UC, mouse models of colitis and CRC and mice deficient for the epithelial-to-mesenchymal transition factor ZEB1 and the DNA repair glycosylase N-methyl-purine glycosylase (MPG). Samples were analysed by immunostaining, qRT-PCR, chromatin immunoprecipitation assays, microbiota next-generation sequencing and ROS determination.
Results : ZEB1 was induced in the colonic epithelium of UC and of mouse models of colitis. Compared with wild-type counterparts, Zeb1-deficient mice were partially protected from experimental colitis and, in a model of inflammatory CRC, they developed fewer tumours and exhibited lower levels of DNA damage (8-oxo-dG) and higher expression of MPG. Knockdown of ZEB1 in CRC cells inhibited 8-oxo-dG induction by oxidative stress (H2O2) and inflammatory cytokines (interleukin (IL)1β). ZEB1 bound directly to the MPG promoter whose expression inhibited. This molecular mechanism was validated at the genetic level and the crossing of Zeb1-deficient and Mpg-deficient mice reverted the reduced inflammation and tumourigenesis in the former. ZEB1 expression in CRC cells induced ROS and IL1β production by macrophages that, in turn, lowered MPG in CRC cells thus amplifying a positive loop between both cells to promote DNA damage and inhibit DNA repair.
Conclusions : ZEB1 promotes colitis and inflammatory CRC through the inhibition of MPG in epithelial cells, thus offering new therapeutic strategies to modulate inflammation and inflammatory cancer.

First Authors:
Oriol de Barrios,Lidia Sanchez-Moral,Marlies Cortés

Correspondence Authors:
Douglas C Dean,Antonio Postigo

All Authors:
Oriol de Barrios,Lidia Sanchez-Moral,Marlies Cortés,Chiara Ninfali,Nuria Profitós-Pelejà,MC Martínez-Campanario,Laura Siles,Rosa Del Campo,María Jesús Fernández-Aceñero,Douglas S Darling,Antoni Castells,Joan Maurel,Azucena Salas,Douglas C Dean,Antonio Postigo

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