Overexpression of homeobox gene HOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells
Overexpression of homeobox gene HOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells
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DOI：
10.1002/ijc.1357
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发表时间：
2001-08-15
影响因子：
6.4
通讯作者：
Moriuchi, T
中科院分区：
文献类型：
--
作者：
Hamada, J;Omatsu, T;Moriuchi, T
含有同源异型框的基因在胚胎发生过程中以时空方式表达，并作为主转录调节因子，其控制参与形态发生的多种基因的表达。它们也以组织特异性方式在正常成人组织中表达，并且似乎在维持其结构完整性方面给予细胞空间信息。我们将HOXD 3 I类同源框基因转染到人肺癌A549细胞中，并研究了HOXD 3过表达A549细胞中与组织结构维持相关的基因表达和表型的改变。在HOXD 3过表达的细胞系中，E-钙粘蛋白的表达丢失，斑珠蛋白被强烈抑制，而整合素α 3和β 3被上调，N-钙粘蛋白和整合素α 4被新表达。与亲本和对照转染细胞系相比，HOXD 3过表达细胞系表现出高度的运动和侵袭活性。使用抗整合素β 1和β 3的阻断实验表明，HOXD 3过表达细胞对玻连蛋白的趋合性增加是由于整合素α v β 3的表达和激活增加，并且HOXD 3基因的过表达将整合素β 1依赖性对纤连蛋白的趋合性转化为整合素β 1和β 3依赖性。HOXD 3过表达增加了基质降解酶的产生，包括基质金属蛋白酶-2和尿激酶-纤溶酶原激活剂。当将肿瘤细胞静脉注射到裸鼠的尾静脉中时，与对照转染子相比，HOXD 3转染子在肺中形成了显著大量的转移灶。这些发现表明HOXD 3可以在人肺癌A549细胞中充当转移促进基因，（C）2001 Wiley-Liss。Inc.
Homeobox-containing genes are expressed in spatiotemporal fashion during embryogenesis and act as master transcription-regulating factors which control the expression of a variety of genes involved in morphogenesis. They are also expressed in a tissue-specific manner in normal adult tissues and appear to give cells spatial information in the maintenance of their architectural integrity. We transfected a HOXD3 class I homeobox-containing gene into human lung cancer A549 cells and investigated alterations in gene expressions and phenotypes related to the maintenance of tissue architecture in HOXD3-overexpressing A549 cells. In the HOXD3-overexpressing cell lines, expression of E-cadherin was lost and plakoglobin was strongly repressed, whereas integrin alpha3 and beta3 were up-regulated and N-cadherin and integrin alpha4 were newly expressed. Compared with parental and control transfectant lines, the HOXD3-overexpressing cell lines showed highly motile and invasive activity. Blocking experiments using anti-integrin beta1 and beta3 suggested that the increased haptotaxis of the HOXD3-overexpressing cells to vitronectin resulted from increased expression and activation of integrin alphav beta3, and that overexpression of the HOXD3 gene converted the integrin beta1-dependent haptotaxis to fibronectin into both integrin beta1- and beta3-dependent one. HOXD3 overexpression increased production of matrix-degrative enzymes including matrix metalloproteinase-2 and urokinase-plasminogen activator. When the tumor cells were intravenously injected into the tail veins of nude mice, HOXD3 transfectants formed a significantly large number of metastatic foci in lungs compared with the control transfectants. These findings suggest that HOXD3 can act as a metastasis-promoting gene in human lung cancer A549 cells, (C) 2001 Wiley-Liss. Inc.