Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice.
Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice.
复制标题
肠道粘蛋白型 O-糖基化缺陷导致小鼠自发性结肠炎相关癌症。
DOI：
10.1053/j.gastro.2016.03.039
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发表时间：
2016-07
期刊：
影响因子：
29.4
通讯作者：
Xia L
中科院分区：
文献类型：
--
作者：
Bergstrom K;Liu X;Zhao Y;Gao N;Wu Q;Song K;Cui Y;Li Y;McDaniel JM;McGee S;Chen W;Huycke MM;Houchen CW;Zenewicz LA;West CM;Chen H;Braun J;Fu J;Xia L
背景与目标
核心1和核心3衍生的粘蛋白型O-连接寡糖（O-聚糖）是结肠粘液层的主要组分。溃疡性结肠炎和结直肠癌患者中经常观察到结肠O-聚糖的缺陷形式，如新生（Tn）抗原，但尚不清楚它们是否有助于其发病机制。我们研究了受损的O-糖基化是否以及如何有助于结肠炎相关的结直肠癌的发展，使用缺乏肠核心1和核心3衍生的O-聚糖的小鼠。
方法
我们产生了缺乏核心1-和核心3-衍生的肠O-聚糖的小鼠（DKO小鼠），并将它们与单独缺乏肠上皮核心1 O-聚糖的小鼠（IEC C1 galt 1（-/-）小鼠）或核心3 O-聚糖的小鼠（C3 Gnt（-/-）小鼠）一起沿着分析。在不同时间点收集肠组织，并使用成像、定量聚合酶链反应、免疫印迹和酶联免疫吸附测定技术分析粘蛋白和Tn抗原的水平、结肠炎的发展和肿瘤形成。我们还使用细胞和遗传方法以及肠道微生物群耗竭来鉴定导致DKO和野生型同窝仔（对照）疾病的炎症介质和途径。
结果
DKO小鼠的肠组织中含有较高水平的Tn抗原，并且比IEC C1 galt 1（-/-）小鼠的组织具有更严重的自发性慢性结肠炎，而C3 GnT（-/-）和对照小鼠中不存在自发性结肠炎。IEC C1 galt 1（-/-）小鼠和DKO小鼠发生自发性结直肠肿瘤，尽管DKO小鼠中的肿瘤发生早于IEC C1 galt 1（-/-）小鼠（15月龄）（8-9月龄）。微生物群的抗生素消耗不会导致Tn抗原的损失，但确实减少了DKO小鼠中结肠炎和癌症形成的发展。来自DKO小鼠的结肠组织，而不是对照小鼠，含有活性形式的半胱天冬酶1和增加的半胱天冬酶11，其在抗生素给药后减少。与对照小鼠相比，DKO小鼠结肠组织上清液中白细胞介素-1 β和白细胞介素-18水平升高。与DKO小鼠相比，DKO小鼠（DKO/Casp 1/11（-/-）小鼠）中caspase 1和caspase 11基因的破坏减少了结肠炎和癌症的发生，其特征在于结肠增厚、增生、炎性浸润和肿瘤减少。
结论
0-聚糖表达受损导致结肠粘液屏障破坏和随后微生物群介导的小鼠结肠上皮细胞中半胱天冬酶1依赖性炎性体的活化。这些过程可能导致人类结肠炎相关结肠癌。
BACKGROUND & AIMS
Core 1- and core 3-derived mucin-type O-linked oligosaccharides (O-glycans) are major components of the colonic mucus layer. Defective forms of colonic O-glycans, such as the Thomsen-nouveau (Tn) antigen, frequently are observed in patients with ulcerative colitis and colorectal cancer, but it is not clear if they contribute to their pathogenesis. We investigated whether and how impaired O-glycosylation contributes to the development of colitis-associated colorectal cancer using mice lacking intestinal core 1- and core 3-derived O-glycans.
METHODS
We generated mice that lack core 1- and core 3-derived intestinal O-glycans (DKO mice) and analyzed them, along with mice that singly lack intestinal epithelial core 1 O-glycans (IEC C1galt1(-/-) mice) or core 3 O-glycans (C3Gnt(-/-) mice). Intestinal tissues were collected at different time points and analyzed for levels of mucin and Tn antigen, development of colitis, and tumor formation using imaging, quantitative polymerase chain reaction, immunoblot, and enzyme-linked immunosorbent assay techniques. We also used cellular and genetic approaches, as well as intestinal microbiota depletion, to identify inflammatory mediators and pathways that contribute to disease in DKO and wild-type littermates (controls).
RESULTS
Intestinal tissues from DKO mice contained higher levels of Tn antigen and had more severe spontaneous chronic colitis than tissues from IEC C1galt1(-/-) mice, whereas spontaneous colitis was absent in C3GnT(-/-) and control mice. IEC C1galt1(-/-) mice and DKO mice developed spontaneous colorectal tumors, although the onset of tumors in the DKO mice occurred earlier (age, 8-9 months) than that in IEC C1galt1(-/-) mice (15 months old). Antibiotic depletion of the microbiota did not cause loss of Tn antigen but did reduce the development of colitis and cancer formation in DKO mice. Colon tissues from DKO mice, but not control mice, contained active forms of caspase 1 and increased caspase 11, which were reduced after antibiotic administration. Supernatants from colon tissues of DKO mice contained increased levels of interleukin-1β and interleukin-18, compared with those from control mice. Disruption of the caspase 1 and caspase 11 genes in DKO mice (DKO/Casp1/11(-/-) mice) decreased the development of colitis and cancer, characterized by reduced colonic thickening, hyperplasia, inflammatory infiltrate, and tumors compared with DKO mice.
CONCLUSIONS
Impaired expression of O-glycans causes colonic mucus barrier breach and subsequent microbiota-mediated activation of caspase 1-dependent inflammasomes in colonic epithelial cells of mice. These processes could contribute to colitis-associated colon cancer in humans.
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影响因子：
24.5
作者：
Andus, T;Daig, R;Gross, V
通讯作者：
Gross, V
影响因子：
15.8
作者：
Heazlewood CK;Cook MC;Eri R;Price GR;Tauro SB;Taupin D;Thornton DJ;Png CW;Crockford TL;Cornall RJ;Adams R;Kato M;Nelms KA;Hong NA;Florin TH;Goodnow CC;McGuckin MA
通讯作者：
McGuckin MA
DOI：
10.1073/pnas.1016814108
发表时间：
2010-12-14
影响因子：
11.1
作者：
Hu, Bo;Elinav, Eran;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
CXCR2 的抑制可显着抑制炎症驱动和自发性肿瘤发生
影响因子：
15.9
作者：
Jamieson, Thomas;Clarke, Mairi;Sansom, Owen J.
通讯作者：
Sansom, Owen J.
影响因子：
29.4
作者：
Itzkowitz, SH;Young, E;Sachar, DB
通讯作者：
Sachar, DB