Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells
Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells
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DOI：
10.1016/j.yexcr.2006.12.020
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发表时间：
2007-03-10
影响因子：
3.7
通讯作者：
Yang, Weng-Lang
中科院分区：
文献类型：
--
作者：
Deng, Haiyun;Makizumi, Ryouji;Yang, Weng-Lang
骨形态发生蛋白（Bone morphogenetic protein， BMP）是tgf - β超家族的一员，参与了骨发育、形态发生、细胞增殖和细胞凋亡。BMP信号的失调已被认为与肿瘤发生有关。通过免疫组化对人结肠正常粘膜和不同分期肿瘤的分析，我们发现晚期腺癌组织中BMP-4的染色强度比正常粘膜和腺瘤组织强，而其受体（BMPR-IA和BMPR-II）在各分期的染色没有差异。在另一组肿瘤组织中，通过实时RT-PCR进一步验证了BMP-4的上调，发现原发性结肠癌伴肝转移的BMP-4 mRNA水平显著高于匹配的正常粘膜。为了了解BMP-4表达在结肠癌进展中的功能相关性，我们从HCT116细胞中生成了BMP-4过表达的细胞克隆。过表达BMP-4不影响HCT116细胞的生长。过表达BMP-4的细胞对血清饥饿诱导的细胞凋亡产生抗性，并表现出增强的迁移和侵袭特性。BMP-4的过表达使细胞形态转变为侵袭性梭形表型，并诱导尿激酶纤溶酶原激活物（uPA）的表达和活性。这些结果表明BMP-4在结肠癌的进展过程中具有侵袭性表型。(c) 2007爱思唯尔公司版权所有。
Bone morphogenetic protein (BMP), a member of the TGF-beta superfamily, is involved in development, morphogenesis, cell proliferation and apoptosis. Dysregulation of BMP signaling has been suggested in tumorigenesis. In an analysis of human colon normal mucosa and tumors at different stages by immunohistochemistry, we observed that the intensity of BMP-4 staining in late-adenocarcinomas was stronger than that in normal mucosa and adenomas, while there was no difference in the staining of its receptors (BMPR-IA and BMPR-II) at all stages. The up-regulation of BMP-4 was further validated in another panel of tumor tissues by real-time RT-PCR, showing that BMP-4 mRNA levels in primary colonic carcinomas with liver metastasis were significantly higher than that in the matched normal mucosa. In order to understand the functional relevance of BMP-4 expression in colon cancer progression, BMP-4-overexpressing cell clones were generated from HCT116 cells. Overexpression of BMP-4 did not affect the HCT116 cell growth. The cells overexpressing BMP-4 became resistant to serum -starvation-induced apoptosis and exhibited enhanced migration and invasion characteristics. Overexpression of BMP-4 changed cell morphology to invasive spindle phenotype and induced the expression and activity of urokinase plasminogen activator (uPA). These results indicate that BMP-4 confers invasive phenotype during progression of colon cancer. (c) 2007 Elsevier Inc. All rights reserved.