Induction of the Angiogenic Phenotype by Hox D3

Boudreau, Nancy; Andrews, Catherine A.; Srebrow, Anabella; Ravanpay, Ali C.; Cheresh, David A.

doi:10.1083/jcb.139.1.257

Cited by 203 publications

(193 citation statements)

References 38 publications

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“…17 Boudreau et al 29 also reported that human endothelial cells transfected with HOXD3 gene expressed integrin ␤3. In the present study, we confirmed the induction of integrin ␤3 by HOXD3-overexpression in a different cell line, and further made it clear that integrin ␤3 induced by HOXD3 played a key role in the enhanced migration of A549 cells to extracellular matrix components such as fibronectin, vitronectin and fibrinogen but not to laminin.…”

Section: Matrix-degradative Property Of the Hoxd3 Transfectantmentioning

confidence: 97%

Overexpression of homeobox geneHOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells

et al. 2001

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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 ␣3 and ␤3 were up-regulated and N-cadherin and integrin ␣4 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 ␤1 and ␤3 suggested that the increased haptotaxis of the HOXD3-overexpressing cells to vitronectin resulted from increased expression and activation of integrin ␣v␤3, and that overexpression of the HOXD3 gene converted the integrin ␤1-dependent haptotaxis to fibronectin into both integrin ␤1-and ␤3-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.

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Section: Matrix-degradative Property Of the Hoxd3 Transfectantmentioning

confidence: 97%

Overexpression of homeobox geneHOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells

et al. 2001

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“…The expression of integrins avb3 and a5b1 partially controls angiogenesis; neither integrin is expressed by quiescent endothelium and both are expressed in response to angiogenic growth factors (Brooks et al, 1994a;Kim et al, 2000a, b). Their expression is controlled by the transcription factor Hox D3 (Boudreau et al, 1997;Boudreau and Varner, 2003;Zhong et al, 2003). Hox D3 is a Homeobox gene expressed by ECs that may regulate an angiogenic switch.…”

Section: Integrins Regulate Angiogenesismentioning

confidence: 99%

“…Hox D3 is a Homeobox gene expressed by ECs that may regulate an angiogenic switch. When expressed in vivo, Hox D3 promotes a haemangioma-like proliferation of blood vessels (Boudreau et al, 1997;Zhong et al, 2003); this transcription factor promotes the expression of integrin avb3, a5b1 and uPA, molecules with established roles in angiogenesis. Thus, Hox D3 may provide a switch to activate a program of angiogenesis.…”

Section: Integrins Regulate Angiogenesismentioning

confidence: 99%

Integrins: roles in cancer development and as treatment targets

2004

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The integrin family of cell adhesion proteins promotes the attachment and migration of cells on the surrounding extracellular matrix (ECM). Through signals transduced upon integrin ligation by ECM proteins or immunoglobulin superfamily molecules, this family of proteins plays key roles in regulating tumour growth and metastasis as well as tumour angiogenesis. Several integrins play key roles in promoting tumour angiogenesis and tumour metastasis. Antagonists of several integrins (a5b1, avb3 and avb5) are now under evaluation in clinical trials to determine their potential as therapeutics for cancer and other diseases.

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“…We have provided evidence that transduction of HOXD3 gene into human erythroleukemia HEL cells leads expression of integrin β3 which forms heterodimer with αIIb [14]. Boudreau et al also have observed that integrin β3 is one of the target genes for HOXD3 in their experiment using human endothelial cells [15]. Further, our previous study has shown that human lung cancer A549 cells overexpressing HOXD3 gene enhance the expressions of N-cadherin and integrins such as α3, α4 and β3 subunits, and eliminate E-cadherin expression [16].…”

Section: Introductionmentioning

confidence: 99%

HOXD3-overexpression increases integrin αvβ3 expression and deprives E-cadherin while it enhances cell motility in A549 cells

Ohta

Hamada

Tada

et al. 2006

Clin Exp Metastasis

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We have previously shown that transduction of HOXD3, one of homeobox genes, into human lung cancer A549 cells enhances cell motility, invasion and metastasis. In the present study, we examined the roles of integrin β3 which was up-regulated by HOXD3-overexpression in the HOXD3-induced motility of A549 cells. We first established integrin β3-transfectants and compared their motile activity to those of the HOXD3-transfected, control-transfected and parental cells by three different assays.The integrin β3-transfectants as well as the HOXD3-transfectants formed heterodimer with integrin αv subunit, and showed highly motile activities assessed by haptotaxis or phagokinetic track assay compared to the control transfectants or parental cells. In vitro wound-healing assay revealed that migratory activities were graded as the HOXD3-transfectants > the integrin β3-transfectants > the control transfectants or parental cells. E-cadherin was expressed in the integrin β3-transfectants but not expressed in the HOXD3-transfectants. An addition of function-blocking antibody to E-cadherin into the wound-healing assay promoted the migratory activity of the integrin β3-transfectants, suggesting that E-cadherin prevented the cells from dissociating from the wound edges. These results indicate that increased expression of integrin αv β3 and loss of E-cadherin by HOXD3-overexpression are responsible for the enhanced motility and dissociation.

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Induction of the Angiogenic Phenotype by Hox D3

Cited by 203 publications

References 38 publications

Overexpression of homeobox geneHOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells

Overexpression of homeobox geneHOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells

Integrins: roles in cancer development and as treatment targets

HOXD3-overexpression increases integrin αvβ3 expression and deprives E-cadherin while it enhances cell motility in A549 cells

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