Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells.
Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells.
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毒蕈碱受体激动剂刺激基质金属蛋白酶1依赖性侵袭人结肠癌细胞。
DOI：
10.1016/j.bbrc.2011.10.052
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发表时间：
2011-11-18
影响因子：
3.1
通讯作者：
Xie, Guofeng
中科院分区：
文献类型：
--
作者：
Raufman, Jean-Pierre;Cheng, Kunrong;Saxena, Neeraj;Chandi, Ahmed;Belo, Angelica;Khurana, Sandeep;Xie, Guofeng
降解细胞外基质的哺乳动物基质金属蛋白酶（MMPs）促进结肠癌细胞侵入血流和结肠外组织;特别地，MMP 1表达与晚期结肠癌阶段、血行转移和不良预后强烈相关。同样，毒蕈碱受体信号传导在结肠癌中起重要作用;与正常结肠上皮细胞相比，毒蕈碱受体在结肠癌中过表达。毒蕈碱受体激活刺激人结肠癌细胞增殖、迁移和侵袭。在小鼠肠肿瘤模型中，毒蕈碱受体的基因消融减弱了癌的发生。在目前的工作中，我们试图通过显示MMP 1的表达和激活在毒蕈碱受体激动剂诱导的结肠癌细胞侵袭中起机械作用来将这些观察结果联系起来。我们发现，乙酰胆碱，这有力地增加MMP 1的表达，刺激HT 29和H508人结肠癌细胞的人脐静脉内皮细胞单层的入侵-这是废除预孵育阿托品，一种非选择性毒蕈碱受体抑制剂，并通过预孵育抗MMP 1中和抗体。使用Matrigel室测定和脱氧胆酰牛磺酸（DCT）获得了类似的结果，DCT是一种与动物模型和人类中结肠肿瘤相关的酰胺化二羟基胆汁酸，先前显示与毒蕈碱受体功能性相互作用。DCT处理人结肠癌细胞导致MMP 1表达的时间依赖性增加10倍，并且DCT诱导的细胞侵袭也被抗MMP 1抗体预处理阻断。这项研究有助于了解毒蕈碱受体激动剂诱导的结肠癌促进的机制，更重要的是，表明阻断MMP 1的表达和激活具有阻止或延缓结肠癌侵袭和扩散的治疗前景。
Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. I n mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers – this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre-treatment with anti-MMP1 antibody. This study contributes to understanding mechanisms underlying muscarinic receptor agonist-induced promotion of colon cancer and, more importantly, indicates that blocking MMP1 expression and activation has therapeutic promise to stop or retard colon cancer invasion and dissemination.
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DOI：
10.1152/ajpgi.90519.2008
发表时间：
2009-04-01
影响因子：
4.5
作者：
Xie, Guofeng;Cheng, Kunrong;Raufman, Jean-Pierre
通讯作者：
Raufman, Jean-Pierre
影响因子：
4.6
作者：
Flynn, Christopher;Montrose, David C.;Rosenberg, Daniel W.
通讯作者：
Rosenberg, Daniel W.
影响因子：
11.2
作者：
Saxena, Neeraj K.;Sharma, Dipali;Anania, Frank A.
通讯作者：
Anania, Frank A.
影响因子：
5.8
作者：
Cheng, KR;Raufman, JP
通讯作者：
Raufman, JP
影响因子：
9.6
作者：
Baker, EA;Bergin, FG;Leaper, DJ
通讯作者：
Leaper, DJ