Bcl-2 Overexpression Induces a Partial Epithelial to Mesenchymal Transition and Promotes Squamous Carcinoma Cell Invasion and Metastasis

Abstract

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. Mol Cancer Res; 8(2); 170-82. ©2010 AACR.

MicroRNA Profile to Predict Gemcitabine Resistance in Bladder Carcinoma Cell Lines

“…35,[39][40][41][42] Expression of these mesenchymal markers increases the migratory capability and invasive potential of the cells. [43][44][45] Interestingly, pancreatic cell lines resistant to gemcitabine also showed EMT characteristics, and re-expression of the miR-200 family resulted in a decrease in Zeb1, Slug, and vimentin, consistent with a reversal of EMT. 15 Depending on the resistant cell line tested, we saw similar results (data not shown).…”

The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

“…To our knowledge, this is the first report demonstrating that the prosurvival Bcl-2 proteins are direct targets of the p53/p21 complex. In addition to cell invasion and death, prosurvival Bcl-2 proteins can regulate various other cellular functions, including autophagy (24)(25)(26)(27), senescence (28)(29)(30), and the epithelial-mesenchymal transition (31)(32)(33)(34). Notably, these cellular functions are also regulated by p53 and p21 (1,2,30,(35)(36)(37)(38)(39).…”

Overexpression of CXCR4 promotes invasion and migration of non‑small cell lung cancer via EGFR and MMP‑9

“…In the Transwell migration assay, as previously described (21,25), the underside of the Transwell insert (pore size, 8 µm; Costar; Corning Incorporated, Corning, NY, USA) was pre-coated with collagen type I (Col-I, 1 µg/ml) or fibronectin (10 µg/ml). Subsequently, 2x10…”

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