Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation.
Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation.
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DOI：
10.1084/jem.20120239
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发表时间：
2012-07-02
期刊：
影响因子：
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通讯作者：
Powrie FM
中科院分区：
文献类型：
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作者：
Boulard O;Kirchberger S;Royston DJ;Maloy KJ;Powrie FM
一个作用于造血细胞的基因位点调节细胞因子表达和粒细胞募集，赋予肝螺杆菌诱导的先天性结肠炎和相关癌症模型的易感性。慢性肠道炎症与患结直肠癌的风险增加有关。最近的关联研究强调了遗传易感性在结肠炎病因学中的作用，并开始揭示其复杂性。然而，影响从结肠炎症到肿瘤发生进展的遗传因素尚不清楚。我们报告了在129.RAG−/−小鼠模型中鉴定调节肝螺杆菌诱导的结肠炎和相关癌症易感性的遗传间隔Hiccs。3号染色体上的1.7 Mb同源间隔，包含8个基因和5个microRNA，使易感小鼠对结肠炎具有抗性，并降低肿瘤发病率和多样性。骨髓嵌合体实验表明，耐药性是由造血隔室赋予的。此外，Hiccs基因座通过调节Thy 1+先天性淋巴细胞的细胞因子表达和粒细胞募集来控制先天性炎症反应的诱导。利用一个结合慢性肝螺杆菌感染和致癌物氧化偶氮甲烷的肿瘤促进模型，我们发现Hiccs也调节结肠炎相关肿瘤的发生频率。我们的研究强调了先天免疫细胞及其遗传结构在驱动炎症向癌症进展中的重要性，并为分析人类炎症性疾病和相关癌症中的这些途径打开了大门。
A genetic locus acting in hematopoietic cells regulates cytokine expression and granulocyte recruitment to confer susceptibility in a Helicobacter hepaticus–induced model of innate colitis and associated cancer. Chronic inflammation of the intestine has been associated with an elevated risk of developing colorectal cancer. Recent association studies have highlighted the role of genetic predisposition in the etiology of colitis and started to unravel its complexity. However, the genetic factors influencing the progression from colon inflammation to tumorigenesis are not known. We report the identification of a genetic interval Hiccs that regulates Helicobacter hepaticus–induced colitis and associated cancer susceptibility in a 129.RAG−/− mouse model. The 1.7-Mb congenic interval on chromosome 3, containing eight genes and five microRNAs, renders susceptible mice resistant to colitis and reduces tumor incidence and multiplicity. Bone marrow chimera experiments showed that resistance is conferred by the hematopoietic compartment. Moreover, the Hiccs locus controls the induction of the innate inflammatory response by regulating cytokine expression and granulocyte recruitment by Thy1+ innate lymphoid cells. Using a tumor-promoting model combining chronic Helicobacter hepaticus infection and the carcinogen azoxymethane, we found that Hiccs also regulates the frequency of colitis-associated neoplasia. Our study highlights the importance of innate immune cells and their genetic configuration in driving progression from inflammation toward cancer and opens the door for analysis of these pathways in human inflammatory disorders and associated cancers.
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影响因子：
29.4
作者：
Asquith MJ;Boulard O;Powrie F;Maloy KJ
通讯作者：
Maloy KJ
DOI：
10.1073/pnas.0404132101
发表时间：
2004-10-26
影响因子：
11.1
作者：
Ea, CK;Sun, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
影响因子：
56.9
作者：
Duerr, Richard H.;Taylor, Kent D.;Cho, Judy H.
通讯作者：
Cho, Judy H.
影响因子：
24.5
作者：
Garrity-Park, M. M.;Loftus, E. V., Jr.;Smyrk, T. C.
通讯作者：
Smyrk, T. C.
影响因子：
64.8
作者：
通讯作者：
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