Gli1, downregulated in colorectal cancers, inhibits proliferation of colon cancer cells involving Wnt signalling activation
Gli1, downregulated in colorectal cancers, inhibits proliferation of colon cancer cells involving Wnt signalling activation
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DOI：
10.1136/gut.2005.080333
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发表时间：
2006-07-01
期刊：
影响因子：
24.5
通讯作者：
Katano, M.
中科院分区：
文献类型：
--
作者：
Akiyoshi, T.;Nakamura, M.;Katano, M.
背景：90%的散发性结直肠癌进展的早期事件依赖于Wnt信号的组成性激活。最近的数据还表明，刺猬（Hh）和Wnt通路在结肠上皮细胞分化之间的密切关联Aims：为了研究是否Gli 1，Hh信号的反式激活因子的表达，可以抑制Wnt信号和抑制人大肠癌cells.Methods：Gli 1和细胞核β-catenin的表达在一系列的40人大肠癌免疫组化检测。我们分别定量Gli 1和细胞核β-连环蛋白染色作为Hh和Wnt通路激活的标志物。使用分别在APC和β-连环蛋白中具有突变的两种人结肠癌细胞系SW 480和HCT 116。Gli 1过表达对Wnt转录活性、β-catenin亚细胞分布和这些细胞增殖的影响进行了分析。结果：在40例人结直肠癌中，B- catenin的核积聚和Gli 1染色水平呈负相关。Gli 1转染细胞中Wnt转录活性降低。甚至在与突变的β-连环蛋白共转染的Gli 1转染细胞中也观察到这些效应。此外，与空载体转染的细胞相比，β-连环蛋白的核积聚减少，并且在Gli 1转染的细胞中观察到c-Myc的转录下调。Gli 1转染细胞的增殖也显着抑制相比，在空载体转染cells.Conclusions：我们的数据表明，Gli 1发挥了抑制作用，在发展中的结直肠癌涉及Wnt信号，即使在稳定突变的B-连环蛋白的情况下。
Background: Early events in the progression of 90% of sporadic colorectal cancers depend on constitutive activation of Wnt signalling. Recent data also indicate a close association between the Hedgehog (Hh) and Wnt pathways in colonic epithelial cell differentiation.Aims: To investigate whether expression of Gli1, a transactivator of Hh signalling, can suppress Wnt signalling and inhibit proliferation of human colorectal cancer cells.Methods: Gli1 and nuclear beta-catenin expression were examined in a series of 40 human colorectal cancers by immunohistochemistry. We quantified Gli1 and nuclear beta-catenin staining as markers of Hh and Wnt pathway activation, respectively. Two human colon cancer cell lines, SW480 and HCT116, with mutations in APC and beta-catenin, respectively, were used. The effects of Gli1 overexpression on Wnt transcriptional activity, beta-catenin subcellular distribution, and proliferation in these cells were analysed.Results: Nuclear accumulation of b- catenin and the Gli1 staining level were inversely associated in the 40 human colorectal cancers. Wnt transcriptional activity was reduced in Gli1 transfected cells. These effects were observed even in Gli1 transfected cells cotransfected with mutated beta-catenin. Furthermore, nuclear accumulation of beta-catenin was diminished compared with that in empty vector transfected cells, and downregulated transcription of c-Myc was observed in Gli1 transfected cells. Proliferation of Gli1 transfected cells was also significantly suppressed compared with that in empty vector transfected cells.Conclusions: Our data suggest that Gli1 plays an inhibitory role in the development of colorectal cancer involving Wnt signalling, even in cases with the stabilising mutation of b- catenin.