Abstract
Homeobox genes regulate sets of genes that determine cellular fates in embryonic morphogenesis and maintenance of adult tissue architecture by regulating cellular motility and cell-cell interactions. Our previous studies showed that a specific member, HOXD3, when overexpressed, upregulates integrin β3 expression in human erythroleukemia HEL cells and lung cancer A549 cells, and enhances their motility and invasiveness. We performed a microarray study of over 7075 genes to determine the mechanisms underlying the HOXD3-enhanced motility and invasiveness in A549 cells. RT–PCR-based tracking gene analyses highlighted a set of TGF-β-upregulated genes, which included matrix metalloproteinase-2, syndecan-1, CD44, and TGF-β-induced 68 kDa protein. Exogenous TGF-β also caused this pattern of upregulation in A549 cells and enhanced their migratory and invasive activity, confirming the involvement of TGF-β signaling. However, HOXD3 reduced the expression of TGF-β-independent genes coding for desmosomal components such as desmoglein, desmoplakin and plakoglobin which are known to suppress tumor invasion and metastasis. These results suggest that HOXD3 enhances the invasive and metastatic potential of cancer cells through the TGF-β-dependent and -independent pathways.
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Acknowledgements
The authors wish to thank Ms. Masako Yanome for help in preparing the manuscript. This work was supported by a Grant-in-Aid for Scientific Research (B) and a Grant-in-Aid for Scientific Research on Priority Areas (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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Miyazaki, Y., Hamada, Ji., Tada, M. et al. HOXD3 enhances motility and invasiveness through the TGF-β-dependent and -independent pathways in A549 cells. Oncogene 21, 798–808 (2002). https://doi.org/10.1038/sj.onc.1205126
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DOI: https://doi.org/10.1038/sj.onc.1205126
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