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HOXD3 Enhances Motility and Invasiveness Through the TGF-B-Dependent and -Independent Pathways in A549 Cells

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HOXD3 Enhances Motility and Invasiveness Through the TGF-B-Dependent and -Independent Pathways in A549 Cells Oncogene (2002) 21, 798 ± 808 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc HOXD3 enhances motility and invasiveness through the TGF-b-dependent and -independent pathways in A549 cells Yasumasa J Miyazaki1,2, Jun-ichi Hamada*,1, Mitsuhiro Tada1, Keiji Furuuchi1, Yoko Takahashi1, Satoshi Kondo2, Hiroyuki Katoh2 and Tetsuya Moriuchi1 1Division of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan; 2Surgical Oncology, Cancer Medicine, Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan Homeobox genes regulate sets of genes that determine regulates the transcription of genes relevant to the cellular fates in embryonic morphogenesis and maintenance formation of speci®c segmental architecture (McGinnis of adult tissue architecture by regulating cellular motility and Krumlauf, 1992). Homeobox-containing genes are and cell-cell interactions. Our previous studies showed that subdivided into more than 20 classes according to their a speci®c member, HOXD3, when overexpressed, upregu- primary sequences. Class I homeobox-containing genes lates integrin b3 expression in human erythroleukemia were the ®rst to be discovered and have been most HEL cells and lung cancer A549 cells, and enhances their extensively studied. In mammals, 39 class I homeobox motility and invasiveness. We performed a microarray genes are clustered in a similar arrangement of 13 study of over 7075 genes to determine the mechanisms paralog groups on four dierent chromosomal/genomic underlying the HOXD3-enhanced motility and invasiveness regions, HOXA, B, C, and D (Graham et al., 1989; in A549 cells. RT ± PCR-based tracking gene analyses Apiou et al., 1996; Mark et al., 1997). They are highlighted a set of TGF-b-upregulated genes, which expressed in a spatiotemporal manner during embryo- included matrix metalloproteinase-2, syndecan-1, CD44, nic morphogenesis, each regulating a group of genes and TGF-b-induced 68 kDa protein. Exogenous TGF-b involved in modeling a speci®c segmental architecture. also caused this pattern of upregulation in A549 cells and Class I homeobox-containing genes have also been enhanced their migratory and invasive activity, con®rming demonstrated in normal adult tissues with character- the involvement of TGF-b signaling. However, HOXD3 istic patterns, suggesting their possible role in the reduced the expression of TGF-b-independent genes coding maintenance of tissue-speci®c architecture (Cillo et al., for desmosomal components such as desmoglein, desmo- 1992; Cillo, 1994 ± 1995). plakin and plakoglobin which are known to suppress tumor The deregulated expressions of HOX genes have invasion and metastasis. These results suggest that HOXD3 been observed in certain cancers. In acute myeloid enhances the invasive and metastatic potential of cancer leukemia, a chromosomal translocation results in the cells through the TGF-b-dependent and -independent fusion of the nuclear pore complex protein NUP98 and pathways. HOXA9 protein, which seems to promote leukemogen- Oncogene (2002) 21, 798 ± 808. DOI: 10.1038/sj/onc/ esis through inhibition of HOXA9-mediated dierentia- 1205126 tion (Borrow et al., 1996; Nakamura et al., 1996a). Proviral activation of Hoxa9 and Hoxa7 by retro- Keywords: homeobox gene; HOXD3; microarray; lung viruses has been shown to be involved in leukemia cancer cells; TGF-b; invasion development in a mouse myeloid leukemia model (Nakamura et al., 1996b). In solid tumors, HOX genes exhibit altered expression patterns in human kidney, Introduction colon and lung cancers, compared to those in normal organs (Cillo et al., 1992, 1999; De Vita et al., 1993; Homeobox-containing genes are the master regulators Tiberio et al., 1994). Altered HOX gene expression is of cell dierentiation and morphogenesis in animals also noted in metastatic lesions of lung and colon (Gehring and Hiromi, 1986). They contain a common cancers, compared to those in their primary lesions sequence element of 183 bp, the homeobox, which (Cillo, 1994 ± 1995; De Vita et al., 1993). encodes a highly conserved 61-amino-acid homeodo- We previously showed that overexpression of the main. The homeodomain is responsible for recognition HOXD3 gene enhanced integrin b3 expression in both and binding of sequence-speci®c DNA motifs, and cis- human erythroleukemia HEL cells and lung carcinoma A549 cells, and that these cells acquired strong ability to adhere to and migrate toward the integrin b3 ligands. However, this ®nding was not observed in the *Correspondence: J-i Hamada; E-mail: [email protected] Received 30 April 2001; revised 2 October 2001; accepted 29 control cells unexpressing HOXD3 gene (Taniguchi et October 2001 al., 1995; Hamada et al., 2001). The HOXD3-over- HOXD3-response genes in human cancer cells YJ Miyazaki et al 799 expressing A549 cells acquired ability to produce large of 6185 genes (87.4%) did not dier between HOX+2 amounts of extracellular matrix-degrading enzymes and Neo1 cells. The remaining 433 genes (6.1%) were including urokinase-type plasminogen activator (uPA) not expressed in either samples. and matrix metalloproteinase-2 (MMP-2), resulting in To verify the microarray results, we performed semi- the enhancement of in vitro cell invasion of Matrigel quantitative RT ± PCR on RNA extracted from the (Hamada et al., 2001). Boudreau et al. (1997) noted the two HOXD3-overexpressing clones (HOX+1 and HOXD3-mediated conversion of endothelium from HOX+2) and two control clones transfected with the resting to an activated angiogenic state. They showed empty vector (Neo1 and Neo2). PCR products that stimulation of endothelial cells with basic separated by agarose gel electrophoresis were stained ®broblast growth factor (bFGF) caused increased with ethidium bromide, and observed under UV light expression of HOXD3, and enhanced expression of (Figure 1). The intensity of each band relative to both the integrin avb3 and uPA in endothelial cells. control was analysed by densitometry. As shown in These lines of evidence suggest that HOXD3 plays a Table 1, the HOXD3-responsive genes indicated by the pivotal role in the regulation of genes related to microarray were classi®ed into ®ve groups: (1) invasion and metastasis. However, these studies remain extracellular matrix (ECM) components; (2) cell incomplete in our attempt of understanding down- adhesion molecules; (3) molecules associated with stream genes of the HOXD3 gene. To better under- ECM-degradation; (4) cytoskeletal system-associated stand the mechanisms of HOXD3-mediated molecules; and (5) growth factors, cytokines and their enhancement of invasive and metastatic potential, we related molecules. Most genes pro®led dierentially by monitored eects of HOXD3-overwxpression on global the microarray analysis were likewise characterized by gene expression by using a human cDNA microarray RT ± PCR. However, in seven gene expressions (Devel- of 7,075 genes. This analysis highlighted the involve- opmental endothelial locus 1, tissue transglutaminase 2, ment of many eectors, especially molecules associated galectin 3, annexin VIII, interferon g-inducible protein with cell-cell and cell-extracellular matrix interactions 16, bone morphogenetic protein 5 and neurotensin), and the activation of a TGF-b-regulated pathway in HOXD3-overexpressing A549 cells. Results Identification of genes responsive to HOXD3 transduction by cDNA microarray analysis We analysed the downstream eects of HOXD3 in A549 cells, using 7075 human cDNA microarrays. A HOXD3-transfected A549 clone (HOX+2) and a control vector-transfected clone (Neo1) were investi- gated as representative cell populations. Of the 7075 genes analysed, 6438 (91.0%) satis®ed the examination criterion (see Materials and methods). In HOX+2 cells, the signal intensities (¯uorescence units) ranged from 127 (Human PDGF-associated protein mRNA, com- plete cds, U41745) to 27 785 (solute carrier family 24 member 1, AF062921). In Neo1 cells, the ¯uorescence signal ranged from 86 (H sapiens mRNA for RP3 gene, AI885178) to 10 638 (solute carrier family 24 member 1, AF062921). The ratios of the relative signal of HOX+2/Neo1 varied from 5.6 (thrombospondin 1, X14787) to 1/3.4 (cystein-rich protein 1, AI433969). Our previous study had revealed that HOXD3-overexpres- sion enhanced the expression of the integrin b3inHEL cells and A549 cells (Taniguchi et al., 1995; Hamada et al., 2001). As expression of the integrin b3 was Figure 1 Expression patterns of representative genes responding upregulated 1.6-fold in the microarray analysis, we to HOXD3-overexpression or TGF-b stimulation. RNA was isolated from HOXD3-overexpressing cells (HOX+1 and regarded the increases in the ratio by more than 1.6-fold HOX+2) and the control transfectant cells (Neo1 and Neo2) as upregulation and the decreases to less than 1/1.6 as which had been treated with TGF-b (0, 0.4, 2 or 10 ng/ml) for downregulation by HOXD3-overexpression. We identi- 24 h. (a) The expression of TGF-b-induced 68 kDa protein (big- ®ed 74 genes (70 cDNAs and four ESTs) (1.0%) as h3) was upregulated by HOXD3 and TGF-b;(b) vitronectin was upregulated (more than 1.6-fold) and 383 genes (167 down-regulated by HOXD3 and TGF-b;(c) HOXD3 was not aected by TGF-b, and integrin b3 was upregulated by HOXD3 cDNAs and 216 ESTs) (5.4%) as downregulated (less but not by TGF-b;(d) plakoglobin was down-regulated by than 1/1.6) by HOXD3-overexpression.
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