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Abstract
Epithelial-mesenchymal transition (EMT) is a process by which cancer cells acquire mesenchymal properties, such as induction of vimentin, while epithelial-associated genes like E-cadherin are lost. This enables cells to be more metastatic. Factors that are able to induce EMT include growth factors such as transforming growth factor-β (TGF-β) and epidermal growth factor, and transcription factors such as Snail. Snail-induced EMT promotes migration and invasion and we hypothesized that this may be mediated by the activity of urokinase-type plasminogen activator (uPA) and its receptor (uPAR). LNCaP, 22Rv1 and ARCaP human prostate cancer (CaP) cells stably transfected with empty vector control (Neo) or constitutively active Snail exhibited increased cell invasion. Superarray analysis revealed an upregulation in uPA and uPAR RNA expression in Snail-transfected ARCaP cells compared with that of a Neo control. In addition, the protein expression levels of Snail, uPA and uPAR were measured by western blot analysis which showed that overexpression of Snail increased uPA and uPAR protein levels. The activity of uPA in conditioned media was measured using an ELISA which revealed that uPA activity was elevated in LNCaP, 22Rv1 and ARCaP cells overexpressing Snail. Additionally, transient silencing of uPAR in ARCaP cells overexpressing Snail using short interfering RNA resulted in abrogation of Snail-mediated invasion. Snail overexpression was associated with increased extracellular-signal-regulated kinase activity, and antagonism of this activity with mitogen-activated protein (MAPK) inhibitor, UO126, inhibited cell invasion and decreased uPA activity. Therefore, Snail-mediated cell invasion in human CaP cells may occur via the regulation of uPA/uPAR and the MAPK signaling pathway.
Highlights
Prostate cancer (CaP) is the most commonly diagnosed malignancy in the United States, with the majority of cases occurring in males over the age of 55 [1]
We have shown that overexpression of Snail increases cell invasion in androgen‐dependent LNCaP and 22RV1 prostate cancer cell lines and androgen‐independent ARCaP prostate cancer cell lines
The results of the superarray demonstrated that the overexpression of Snail leads to upregulation of genes involved with invasion and metastasis, such as urokinase‐type plasminogen activator (uPA) and uPA receptor (uPAR)
Summary
Prostate cancer (CaP) is the most commonly diagnosed malignancy in the United States, with the majority of cases occurring in males over the age of 55 [1]. In 2012, ~241,740 new cases of CaP were predicted to be diagnosed, with ~28,170 men succumbing to CaP, in the United States alone [1]. Tumors that are detected early via testing serum prostate‐specific antigen levels or digital rectal examination may be effectively treated by prostatectomy or radiation therapy [2]. 30% of treated patients suffer relapse and progress to hormone refractory prostate cancer (HRPC), which no longer responds to androgen ablation, whereas early CaP growth is androgen‐dependent. Metastasis is a complex process by which cancer cells leave the primary tumor and migrate to a secondary site where they recolonize. The shortcomings of treatment for such highly invasive and metastatic disease have led to several investigations of various molecular targets that directly affect invasion and metastasis with the aim of developing safe and effective treatments
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