Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4
Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4
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DOI：
10.1073/pnas.1016814108
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
--
作者：
Hu, Bo;Elinav, Eran;Flavell, Richard A.
慢性炎症是已知的肿瘤发生的危险因素，但这种关联的确切机制目前尚不清楚。炎症小体是一种由nod样受体（NLR）家族成员形成的多蛋白复合物，最近被证明可以协调多种先天和适应性免疫反应，但其在炎症诱导的癌症中的潜在作用却很少被研究。通过偶氮甲烷和葡聚糖硫酸钠结肠炎相关结直肠癌模型，我们发现caspase-1缺陷（Casp1(-/-)）小鼠的肿瘤形成增强。令人惊讶的是，caspase-1在肿瘤发生中的作用不是通过调节结肠炎症，而是通过调节结肠上皮细胞的增殖和凋亡。因此，caspase-1缺陷小鼠在损伤诱导肿瘤形成的早期阶段表现出结肠上皮细胞增殖增加，在晚期肿瘤中表现出细胞凋亡减少。我们提出了一个模型，其中NLRC4炎性小体通过调节上皮细胞对损伤的反应在结肠炎症诱导的肿瘤形成中起核心作用。
Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association is currently unknown. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation-induced cancer has been little studied. Using the azoxymethane and dextran sodium sulfate colitis-associated colorectal cancer model, we show that caspase-1-deficient (Casp1(-/-)) mice have enhanced tumor formation. Surprisingly, the role of caspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather through regulation of colonic epithelial cell proliferation and apoptosis. Consequently, caspase-1-deficient mice demonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumor formation and reduced apoptosis in advanced tumors. We suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury.