Evidence shows that Bcl-2 family members play a direct role in the development of some human malignancies.However, the mechanism by which Bcl-2 may influence tumor cell invasion and metastasis remains unclear.Ectopic overexpression of Bcl-2 in the human squamous carcinoma cell line HSC-3 enhanced tumorigenicity and experimental pulmonary metastasis.Interestingly, Bcl-2-expressing cells showed morphologic changes that resembled that of cells with an epithelial-mesenchymal transition phenotype.Analysis revealed increased N-cadherin and vimentin expression in parallel with attenuated E-cadherin level, along with enhanced migration and invasive behavior.Zymography studies confirmed elevated levels of matrix metalloproteinase-9 (MMP-9) in media of Bcl-2-expressing cells, siRNA-mediated suppression of N-cadherin expression not only prevented the enhanced invasion but also blocked the increased MMP-9 expression induced by elevated Bcl-2 expression.Accordingly, pharmacologic inhibition of MMP-9 abrogated the increased tumor cell invasion.Furthermore, the Bcl-2-mediated increase in MMP-9 expression and tumor cell invasion was dependent on fibroblast growth factor receptor-1 or extracellular signal-regulated kinase signaling.Collectively, the data establish that Bcl-2 overexpression in squamous carcinoma cells induces a partial epithelial to mesenchymal transition that promotes not only survival but also invasion and metastasis through the N-cadherin/ fibroblast growth factor receptor/extracellular signal-regulated kinase pathway.