| Co-Investigator(Kenkyū-buntansha) |
OKADA Futoshi Hokkaido Univ., Inst.for Genetic Med., Instructor, 遺伝子病制御研究所, 助手 (00250423)
MORIUCHI Tetsuya Hokkaido Univ., Inst.for Genetic Med., Professor, 遺伝子病制御研究所, 教授 (20174394)
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| Budget Amount *help |
¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 2000: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1999: ¥5,100,000 (Direct Cost: ¥5,100,000)
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| Research Abstract |
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
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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
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