The roles of cell adhesion molecules in the metastasis-related gene network downstream of HOXD3 gene

我们一直从肿瘤细胞同源盒基因异常表达的角度研究肿瘤侵袭转移的机制。我们之前发现，同源盒基因之一HOXD3基因的过表达可将人肺癌A5 49细胞转化为更具运动性、侵袭性和转移性的细胞。我们还发现，在过表达HOXD3基因的A549细胞中，整合素β 3、MMP-2、uPA和E-cadherin等转移相关基因的表达发生了改变。在这项研究中，我们研究了细胞粘附分子在HOXD3基因下游转移相关基因网络中的作用。我们从这项研究中得到了以下结果。1) hoxd3过表达对A549细胞运动的增强依赖于整合素alphavbeta3；2) 30个被hoxd3过表达改变的基因中，有15个基因的表达同样被整合素alphavbeta3的信号改变；3) hoxd3过表达将潜伏的tgf - β转化为活跃的tgf - β，以自分泌方式激活tgf - β受体的信号通路；4) tgf - β刺激A549细胞向I型胶原的体外侵袭和迁移；5)在hoxd3过表达改变的30个转移相关基因中，tgf - β诱导的9个基因表达模式相似。

We have been studying the mechanisms of tumor invasion and metastasis from the viewpoint of abnormal expression of homeobox genes by tumor cells. We previously found that the overexpression of HOXD3 gene, one of the homeobox genes converted human lung cancer A5 49 cells into more motile, invasive and metastatic ones. We also revealed the altered expressions of metastasis-related genes such as integrin beta3, MMP-2, uPA and E-cadherin in A549 cells overexpressing HOXD3 gene. In this study, we examined the roles of cell adhesion molecules in the metastasis-related gene network downstream of the HOXD3 gene. We obtained the following results from this study. 1) Enhanced motility of A549 cells by the HOXD3-overexpression was dependent on integrin alphavbeta3 ; 2) the expressions of 15 of 30 genes of which expressions were altered by the HOXD3-overexpression were similarly changed by the signals through integrin alphavbeta3 ; 3) the HOXD3-overexpression converted latent TGF-beta into active one which activated the sigunaling pathways through TGF-beta receptors in an autocrine manner ; 4) TGF-beta stimulated the in vitro invasion and migration of A549 cells to type I collagen ; 5) TGF-beta induced the similar expression patterns in 9 of 30 metastasis-related genes of which expressions were altered by the HOXD3-overexpression.