Abnormal epithelial-mesenchymal interaction induces disordered HOX gene expression and enhances metastatic capacity

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Hepatocyte growth factor (HGF) is known as a mediator of epithelial cells and mesenchymal cells during morphogenesis in embryo. HOX genes act as master controller during the morphogenesis. Invasion and metastasis are considered to be a phenomenon caused from abnormal epithelial-mesenchymal interaction by morphogenesis-related factors including HGF. In this study, we aimed to demonstrate the hypothesis : HGF results in enhancement of invasion and metastasis by the altered expression of HOX genes which regulate metastasis-related genes. We obtained the following results. When human pancreatic cancer SUIT-2 cells were treated with HGF, E-cadhein, disappeared from cell membranes and β-catenin translocated from cell membrane to nucleus. Real-time quantitative RT-PCR analysis revealed that HGF increased the expression of only HOXB3 gene of 39 HOX genes. The results from luciferase reporter assays indicated that the complex of β-catenin and TCF/Lef1 transcription factor is bound to promoter region of HOXB3 gene and transactivates the gene. Cell biological studies showed that HGF promoted the cell scattering and motility of SUIT-2 cells. We are now analySing the phenotypical changes of SUIT-2 cells transfected with HOXB3 expression vectors to explore the genes of which expressions are regulated by HOXB3.