Loss of intestinal O-glycans promotes spontaneous duodenal tumors
Loss of intestinal O-glycans promotes spontaneous duodenal tumors
复制标题
肠道O-聚糖的损失会促进自发性十二指肠肿瘤。
DOI：
10.1152/ajpgi.00060.2016
复制
发表时间：
2016-07-01
影响因子：
4.5
通讯作者：
Xia, Lijun
中科院分区：
文献类型：
--
作者：
Gao, Nan;Bergstrom, Kirk;Xia, Lijun
粘蛋白型0-聚糖，主要是核心1-和核心3-衍生的0-聚糖，是整个胃肠道的主要粘液屏障组分。先前的报告确定了O-聚糖在胃和结肠中的生物学作用。然而，O-聚糖在小肠中的生物学功能仍然未知。使用缺乏肠核心1-和核心3-源性O-聚糖[肠上皮细胞C1 galt 1（-/-）; C3 GnT（-/-）或双敲除（DKO）]的小鼠，我们发现O-聚糖的缺失使DKO小鼠在11岁时易于发生自发性十二指肠肿瘤。肿瘤发病率并没有随着年龄的增长而增加，但是，肿瘤的侵略性在20个月内。在肿瘤发展之前，0-聚糖缺乏与DKO小鼠的管腔粘液减少相关。通过Ki 67染色测定，肠上皮稳态改变伴基线隐窝增殖增强表征了这些表型。此外，荧光原位杂交分析显示，与大肠相比，十二指肠的细菌负荷显著降低。这种表型在抗生素治疗后没有减少，这意味着O-糖基化缺陷，而不是细菌诱导的炎症，后者导致自发性十二指肠肿瘤发生。此外，DKO十二指肠粘膜的炎症反应是轻微的，如用组织学、炎症相关细胞因子的定量PCR和免疫细胞的免疫染色所测定的。重要的是，成年小鼠肠道O-聚糖的诱导性缺失导致类似的自发性十二指肠肿瘤，尽管与O-聚糖组成性缺失的小鼠相比，其发生率更高，严重程度更高。总之，这些研究表明小肠内的O-聚糖是十二指肠癌风险的关键决定因素。未来的研究将深入了解一般人群和这种罕见但致命的癌症的发病机制。
Mucin-type O-glycans, primarily core 1- and core 3-derived O-glycans, are the major mucus barrier components throughout the gastrointestinal tract. Previous reports identified the biological role of O-glycans in the stomach and colon. However, the biological function of O-glycans in the small intestine remains unknown. Using mice lacking intestinal core 1- and core 3-derived O-glycans [intestinal epithelial cell C1galt1(-/-);C3GnT(-/-) or double knockout (DKO)], we found that loss of O-glycans predisposes DKO mice to spontaneous duodenal tumorigenesis by ∼1 yr of age. Tumor incidence did not increase with age; however, tumors advanced in aggressiveness by 20 mo. O-glycan deficiency was associated with reduced luminal mucus in DKO mice before tumor development. Altered intestinal epithelial homeostasis with enhanced baseline crypt proliferation characterizes these phenotypes as assayed by Ki67 staining. In addition, fluorescence in situ hybridization analysis reveals a significantly lower bacterial burden in the duodenum compared with the large intestine. This phenotype is not reduced with antibiotic treatment, implying O-glycosylation defects, rather than bacterial-induced inflammation, which causes spontaneous duodenal tumorigenesis. Moreover, inflammatory responses in DKO duodenal mucosa are mild as assayed with histology, quantitative PCR for inflammation-associated cytokines, and immunostaining for immune cells. Importantly, inducible deletion of intestinal O-glycans in adult mice leads to analogous spontaneous duodenal tumors, although with higher incidence and heightened severity compared with mice with O-glycans constitutive deletion. In conclusion, these studies reveal O-glycans within the small intestine are critical determinants of duodenal cancer risk. Future studies will provide insights into the pathogenesis in the general population and those at risk for this rare but deadly cancer.