Id‐1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/AKT signaling pathway

Id‐1 (inhibitor of differentiation or DNA binding) is a helix‐loop‐helix protein that is overexpressed in many types of cancer including esophageal squamous cell carcinoma (ESCC). We previously reported that ectopic Id‐1 expression activates the phosphatidylinositol‐3‐kinase (PI3K)/protein kinase B (AKT) signaling pathway in human esophageal cancer cells. In this study, we confirmed a positive correlation between Id‐1 and phospho‐AKT (Ser473) expressions in ESCC cell lines, as well as in ESCC on a tissue microarray. To investigate the significance of Id‐1 in esophageal cancer progression, ESCC cells with stable ectopic Id‐1 expression were inoculated subcutaneously into the flank of nude mice and were found to form larger tumors that showed elevated Ki‐67 proliferation index and increased angiogenesis, as well as reduced apoptosis, compared with control cells expressing the empty vector.The Id‐1‐overexpressing cells also exhibited enhanced metastatic potential in the experimental metastasis assay. Treatment with the PI3K inhibitor LY294002 attenuated the tumor promotion effects of Id‐1, indicating that the effects were mediated by the PI3K/AKT signaling pathway. In addition, our in vitro experiments showed that ectopic Id‐1 expression altered the expression levels of markers associated with epithelial–mesenchymal transition and enhanced the migration ability of esophageal cancer cells. The Id‐1‐overexpressing ESCC cells also exhibited increased invasive potential, which was in part due to PI3K/AKT‐dependent modulation of matrix metalloproteinase‐9 expression. In conclusion, our results provide the first evidence that Id‐1 promotes tumorigenicity and metastasis of human esophageal cancer in vivo and that the PI3K inhibitor LY294002 can attenuate these effects. © 2009 UICC