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Homeobox gene that regulated expressions of metastasis-related genes

调节转移相关基因表达的同源盒基因

基本信息

批准号：
11470053
负责人：
HAMADA Jun-ichi
金额：
$ 4.8万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470053/
关键词：
Homeobox gene Invasion and metastasis integrin HOXD3 cDNA microarray lung cancer cell Cadherin malignant melanoma MMP-2 uPA プラコグロビン CD44

项目摘要

We hypothesized that deregualted expression of homeobox genes would modify the invasive and metastatic ability of tumor cells since the genes act as master genes regulating cellular spatial information during morphogenesis in embryo. In this study, mammalian expression vectors for HOXD3 gene (one of class I homeobox genes) or antisense HOXD3 gene were transduced into human tumor cells.I.mRNA was extracted from HOXD3-overexpressing human lung cancer A549 cells and unexpressing control A549 cells. To collectively analyze the genes in the downstream of HOXD3, we compared gene expression patterns between the two by using cDNA microarray consisting of approximately 7,000 elements. HOXD3-responsive genes indicated by the microarray were to code the following 5 groups : 1) extracellular matrix (ECM) components, 2) cell adhesion molecules, 3) molecules associated with ECM-degradation, 4) cytoskeletal system-associated molecules and 5) growth factors, cytokines and their related molecules. It i … More s noteworthy that HOXD3-overexpression resulted in reduced expression of cell-cell adhesion molecules such as desmoglein, desmoplakin, plakoglobin and E-cadherin and increased expression of molecules associated with cell-extracellular matrix interaction such as integrin α4, β3, CD44, thrombospondin, plasminogen activator inhibitor, MMP-2 and uPA.The altered expression of these genes may result in enhancement of invasion and metastasis in HOXD3-overexpressing A54 9 cells.II.The transduction of HOXD3 antisense into human melanoma A375M cells resulted in reduced cell motility and invasion. To compare gene expression patterns between A375M cells expressing antisense HOXD3 and unexpressing cells, we applied cDNA microarray analysis. The microarray revealed that the transduction of antisense HOXD3 increased expressions of tropomyosin 2 and cdc42-interacting protein 4 which were components of cytoskeletal system.These results indicated that deregulated expression of HOXD3 altered a variety of metastasisrelated genes, especially those coding cell adhesion or cytoskeletal molecules, resulting in enhancing invasion and metastasis. Less

我们推测，由于同源框基因在胚胎形态发生过程中是调节细胞空间信息的主控基因，因此该基因的表达下调可能会改变肿瘤细胞的侵袭和转移能力。本研究将Hoxd3基因(I类同源盒基因之一)或反义Hoxd3基因的真核表达载体导入人肿瘤细胞，从高表达Hoxd3基因的人肺癌A549细胞和未表达的对照A549细胞中提取1.mRNA。为了共同分析Hoxd3下游的基因，我们使用由大约7,000个元件组成的基因芯片比较了两者之间的基因表达模式。芯片显示的Hoxd3应答基因编码5组：1)细胞外基质(ECM)成分，2)细胞黏附分子，3)ECM降解相关分子，4)细胞骨架系统相关分子，5)生长因子、细胞因子及其相关分子。IT I…更值得S注意的是，Hoxd3过表达导致细胞间黏附分子如桥粒蛋白、桥粒蛋白、白蛋白和E-钙粘附素的表达降低，而与细胞-细胞外基质相互作用相关的分子如整合素α4、β3、CD44、凝血酶反应蛋白、纤溶酶原激活物抑制物、基质金属蛋白酶-2和uPA的表达增加，这些基因的表达改变可能导致Hoxd3过表达的A549细胞侵袭和转移增强。为了比较表达反义Hoxd3的A375M细胞和不表达Hoxd3的A375M细胞的基因表达模式，我们应用了基因芯片分析。基因芯片显示，反义Hoxd3基因的转导增加了原肌球蛋白2和CDC42相互作用蛋白4的表达，这些基因是细胞骨架系统的组成部分。这些结果表明，Hoxd3基因的失控表达改变了多种转移相关基因，特别是编码细胞黏附或细胞骨架分子的基因，从而增强了侵袭和转移。较少