HOXD3 enhances motility and invasiveness through the TGF-β-dependent and -independent pathways in A549 cells

Miyazaki, Yasumasa; Hamada, Jun Ichi; Tada, Mitsuhiro; Furuuchi, Keiji; Takahashi, Yōko; Kondo, Satoshi; Katoh, Hiroyuki; Moriuchi, Tetsuya

doi:10.1038/sj.onc.1205126

Cited by 45 publications

(41 citation statements)

References 48 publications

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“…However, the present study has not shown any significant change in expression in either of these genes. These results might be partly explained by the choice of cell type in the present study, and partly due of the activity of other signal pathways, such as the Ras and ERK pathway for cyclin D1 regulation (Pruitt and Der, 2001;Jirmanova et al, 2002), TGF-b and hepatocyte growth factor for CD44 regulation (Miyazaki et al, 2002;Mine et al, 2003).…”

Section: Discussionmentioning

confidence: 85%

MRP-1/CD9 gene transduction downregulates Wnt signal pathways

et al. 2004

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Motility-related protein-1 (MRP-1/CD9) is a transmembrane glycoprotein that has been implicated in cell adhesion, motility, proliferation, and differentiation. It has a functional role as a tumor metastatic suppressor. During tumor progression, a reduction of MRP-1/CD9 gene expression results in tumor cells with a high metastatic potential. However, the mechanism of action of MRP-1/CD9 is still unclear. We studied changes of gene expression in relation to MRP-1/CD9 gene transduction into tumor cell lines, HT1080 and A549, using microarray assays and real-time PCR. Consequently, we have demonstrated that MRP-1/ CD9 gene transduction can downregulate expression of several Wnt family genes, such as Wnt1, Wnt2b1 and Wnt5a, and their target genes, including WISP-1 (Wnt-1 induced secreted protein 1), WISP-3, c-Myc, vascular endothelial growth factor-A, and matrix metalloproteinase-26. Western blot analyses also showed that MRP-1/CD9 gene transduction downregulated expression of Wnt1 protein and its target proteins. In addition, a neutralizing anti-MRP-1/CD9 monoclonal antibody inhibited the downregulation of Wnt signal pathways in MRP-1/CD9-transfected cells. The present study has revealed that the MRP-1/CD9 signal is located upstream of the Wnt signal pathways. Therefore, MRP-1/CD9 could suppress cell transformation including epithelial to mesenchymal transition through downregulation of Wnt1, and might suppress tumor metastasis through downregulation of Wnt5a.

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Section: Discussionmentioning

confidence: 85%

MRP-1/CD9 gene transduction downregulates Wnt signal pathways

et al. 2004

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“…12 Our previous studies showed that human lung cancer A549 cells transfected with HOXD3 gene acquired more metastatic, invasive and motile phenotypes. 13,14 We also observed that the transduction of HOXD3-antisense expression vectors into human melanoma cells dramatically diminished their invasive and motile activities. 15 Taken together, inappropriate expression of a particular HOX gene(s) is likely involved in tumor development and malignant progression such as invasion and metastasis and that the HOX gene(s) responsible for oncogenesis and/or tumor progression differs according to the organs or tissues from which the tumor cells have derived.…”

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confidence: 74%

Altered expressions of HOX genes in human cutaneous malignant melanoma

Maeda

Hamada

Takahashi

et al. 2004

Intl Journal of Cancer

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HOX genes act as master genes to control morphogenesis. In human, HOX genes form 4 clusters composing 9 to 11 HOX genes (39 genes in total) on different chromosomes. We hypothesized that aberrant expression of HOX genes was associated with development and subsequent progression of melanoma and that the 39 HOX gene expression pattern determined the sites where melanoma grew. The expression levels of 39 HOX genes in 15 human cutaneous melanoma specimens and 7 nevus pigmentosus specimens were quantified by a comprehensive analysis system based on the real-time RT-PCR method. We found that the expression levels of HOXA11, A13, B9, D12 and D13 in melanoma were higher than those in nevus pigmentosus and that the expression levels of HOXA11, B2 and C13 were significantly different between pT4 melanoma and pT1 to pT3 melanoma. It was most notable that the expression levels of HOXA1, A2, C4 and B13 in melanoma with distant metastasis were higher than those in melanoma without it. On the other hand, we found no relationship between HOX genes expression patterns and the growing sites of melanoma. These results indicated that the misexpressions of some specific HOX genes were implicated in melanoma genesis and metastasis but had no linkage with melanoma sites. © 2004 Wiley-Liss, Inc. Key words: melanoma; HOX; metastasis; nevus pigmentosusHox genes are one of the master regulators of morphogenesis and cell differentiation during embryogenesis of animals. 1 The genes contain a 180 bp DNA sequence (homeobox), which encodes a highly conserved 60 amino acid homeodomain. The HOX proteins function as transcription factors through their homeodomain, which is responsible for recognition and binding of sequence-specific DNA motifs. 2,3 In human genome, 39 HOX genes are clustered in a similar arrangement of 13 paralog groups in 4 different chromosomal regions, HOXA, B, C and D. 4 During embryonic morphogenesis, the HOX genes determine positional identity along the anterior-posterior and secondary axes in animals. Within each cluster, HOX genes located at the 3Ј extremity are activated first and in anterior embryonic domains, whereas 5Ј-located genes are transcribed subsequently and in more caudal areas, which is the property called colinearity rule. 5 HOX genes are also expressed in some normal adult organs in characteristic patterns, suggesting their possible role in the maintenance of tissuespecific architecture besides their roles in embryogenesis. 6 -9 Comparative analysis of HOX gene expression between cancerous tissues and normal tissues uncovered the dysregulated expression(s) of a particular HOX gene(s) in some kinds of carcinomas. For example, HOXB5 and B9 are expressed in normal kidney but not in renal cancer, whereas the expression of HOXC11 is observed in human renal cancer but not in normal kidney. 6 In human prostate cancer, overexpression of HOXC8 correlates with loss of differentiated phenotype. 10 Increased expressions of HOXC4, C5, C6 and C11 are likely to be involved in the development of human bladder transitiona...

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“…As previously shown, HOXD3-overexpressing A549 cells convert latent TGF-beta into active one, which activates the TGF-β-signaling in an autocrine manner [32].…”

Section: Hoxd3-transfectants Fibronectin Is a Ligand For A Variety Omentioning

confidence: 89%

“…The stimulation with TGF-β enhances haptotaxis of A549 cells to type I collagen but not to vitronectin, fibrinogen or fibronectin [32]. Thus we suppose that HOXD3 enhances cell motility through the TGF-β-dependent and -independent pathways in A549 cells.…”

Section: Hoxd3-transfectants Fibronectin Is a Ligand For A Variety Omentioning

confidence: 92%

“…Taken together with our previous study indicating that HOXD3 directly or indirectly regulates transcriptions of metastasis-related genes such as matrix metalloproteinase-2, urokinase-type plasminogen activator, E-cadherin, desmoglein and others [16,32], HOXD3 can be a master gene of metastasis in A549 cells.…”

Section: Hoxd3-transfectants Fibronectin Is a Ligand For A Variety Omentioning

confidence: 99%

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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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HOXD3 enhances motility and invasiveness through the TGF-β-dependent and -independent pathways in A549 cells

Cited by 45 publications

References 48 publications

MRP-1/CD9 gene transduction downregulates Wnt signal pathways

MRP-1/CD9 gene transduction downregulates Wnt signal pathways

Altered expressions of HOX genes in human cutaneous malignant melanoma

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

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