Loss of hSef promotes metastasis through up-regulation of EMT in prostate cancer

Abstract

We have previously reported that the negative regulator Similar Expression to FGF (hSef) is down-regulated in prostate cancer and its loss is associated with clinical metastasis. Here, we explored the mechanistic basis of this finding. We first confirmed our clinical observation by testing hSef manipulation in an in vivo metastasis model. hSef stable expressing cells (PC3M-hSef) or empty vector controls (PC3M-EV) were injected subcutaneously into the lateral thoracic walls of NOD-SCID gamma mice and lungs were harvested at autopsy. In this model, 6/7 PC3M-EV xenografts had definitive lung micro-metastasis whilst only 1/6 PC3M-hSef xenografts exhibited metastasis recapitulating the clinical scenario (p=0.03). Gene expression studies revealed key perturbations in genes involved in cell motility and epithelial to mesenchymal transition (EMT) along with alterations in cognate signalling pathways. These results were validated in an EMT specific PCR array whereby hSef over-expression and silencing reciprocally altered E-Cadherin expression (p=<0.001) amongst other EMT markers. Immunohistochemistry of excised tumours from the xenografts also confirmed the effect of hSef in suppressing E-Cadherin expression at the protein level. Phosphokinase arrays further demonstrated a role for hSef in attenuating signalling of not only ERK-MAPK but also the JNK and p38 pathways as well. Taken together, these data suggest evidence that loss of hSef may be a critical event facilitating tumour dissemination of prostate cancer through alteration of EMT. Detection of down-regulated hSef, along with other negative regulators, may therefore be a useful biomarker heralding a transition to a metastatic phenotype and warrants further exploration in this context. This article is protected by copyright. All rights reserved.

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