Role for epithelial dysregulation in early-onset colitis-associated colon cancer in Gi2-alpha-/- mice.
Role for epithelial dysregulation in early-onset colitis-associated colon cancer in Gi2-alpha-/- mice.
复制标题
Gi2-α-/- 小鼠上皮失调在早发性结肠炎相关结肠癌中的作用。
DOI：
10.1002/ibd.20414
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发表时间：
2008
影响因子：
4.9
通讯作者：
Birnbaumer,Lutz
中科院分区：
文献类型：
--
作者：
Edwards,RobertA;Wang,Kehui;Davis,JenniferS;Birnbaumer,Lutz
研究背景炎症性肠病（IBD）是结直肠癌的危险因素，但其发病机制尚不清楚。缺乏G蛋白α亚基Gi 2-α的小鼠自发地发展结肠炎和结肠癌，并且具有高转移率。与经典的基于Wnt/APC信号传导的结肠癌动物模型相比，Gi 2-alpha−/−小鼠中的肿瘤更接近于人类IBD相关癌症的特征。他们主要是右侧，多灶性，粘液性，并产生从平坦dysplasia.MethodsIn评估上皮Gi 2-α信号传导到这种表型的潜在贡献，我们发现，Gi 2-α −/−结肠上皮细胞过度增殖，甚至在结肠炎发病前，和耐诱导细胞凋亡。我们产生的结肠癌细胞系过表达显性负Gi 2-alpha.ResultsLike其他细胞缺乏Gi 2-alpha，这些细胞释放较少的花生四烯酸，一个重要的神经元和上皮生长调节。他们也是过度增殖和抵抗喜树碱诱导的细胞凋亡和caspase-3 activation.ConclusionsThe结肠炎相关的癌症Gi 2-alpha−/−小鼠出现非常相似，在人类IBD患者中看到的，和Gi 2-alpha是结肠上皮细胞生长的直接负调节。
BackgroundInflammatory bowel disease (IBD) is a risk factor for developing colorectal cancer but the mechanisms are poorly characterized. Mice lacking the G-protein alpha subunit Gi2-alpha spontaneously develop colitis and colon cancer with high penetrance. Compared to canonical Wnt/APC signaling-based animal models of colon cancer, the tumors in Gi2-alpha−/− mice more closely recapitulate the features of IBD-associated cancers seen in humans. They are predominantly right-sided, multifocal, mucinous, and arise from areas of flat dysplasia.MethodsIn evaluating the potential contribution of epithelial Gi2-alpha signaling to this phenotype, we found that Gi2-alpha−/− colonic epithelium is hyperproliferative even before the onset of colitis, and resistant to the induction of apoptosis. We generated colon cancer cell lines overexpressing dominant-negative Gi2-alpha.ResultsLike other cells lacking Gi2-alpha, these cells release less arachidonic acid, an important antiinflammatory and epithelial growth regulator. They are also hyperproliferative and resistant to camptothecin-induced apoptosis and caspase-3 activation.ConclusionsThe colitis-associated cancers in Gi2-alpha−/− mice appear very similar to those seen in human IBD patients, and Gi2-alpha is a direct negative regulator of colonic epithelial cell growth.