Overexpression of homeobox gene HOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells.
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 alphavbeta3, 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.
Hamada Ji
Division of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Omatsu
T
T
Okada
F
F
Furuuchi
K
K
Okubo
Y
Y
Takahashi
Y
Y
Tada
M
M
Miyazaki
Y J
YJ
Taniguchi
Y
Y
Shirato
H
H
Miyasaka
K
K
Moriuchi
T
T
D015703:Antigens, CD / Q000096:biosynthesis; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D051180:Desmoplakins; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005801:Genes, Homeobox / Q000235:genetics*; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D039422:Integrin alpha3; D039661:Integrin beta3; D016023:Integrins / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis; D019030:Receptors, Vitronectin / Q000096:biosynthesis / Q000502:physiology; D015534:Trans-Activators; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D019096:Vitronectin / Q000502:physiology; D051178:alpha Catenin; D051176:beta Catenin; D051185:gamma Catenin
D015703:Antigens, CD; C495273:CTNNA1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051180:Desmoplakins; D005353:Fibronectins; D018398:Homeodomain Proteins; D039422:Integrin alpha3; D039661:Integrin beta3; D016023:Integrins; D010980:Platelet Membrane Glycoproteins; D019030:Receptors, Vitronectin; D015534:Trans-Activators; D014157:Transcription Factors; D019096:Vitronectin; D051178:alpha Catenin; D051176:beta Catenin; D051185:gamma Catenin; C073547:HOXA4 protein, human