Loss of hSef promotes metastasis through upregulation of EMT in prostate cancerReportar como inadecuado

Loss of hSef promotes metastasis through upregulation of EMT in prostate cancer

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Publication Date: 2017-04-15

Journal Title: International Journal of Cancer

Publisher: Wiley

Volume: 140

Issue: 8

Pages: 1881-1887

Language: English

Type: Article

This Version: VoR

Metadata: Show full item record

Citation: Hori, S., Wadhwa, K., Pisupati, V., Zecchini, V., Ramos-Montoya, A., Warren, A., Neal, D., & et al. (2017). Loss of hSef promotes metastasis through upregulation of EMT in prostate cancer. International Journal of Cancer, 140 (8), 1881-1887. https://doi.org/10.1002/ijc.30604

Abstract: We have previously reported that the negative signaling regulator Similar Expression to FGF (hSef) is downregulated 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 $\textit{in vivo}$ 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 ($\textit{p}$ = 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 signaling pathways. These results were validated in an EMT specific PCR array whereby hSef over-expression and silencing reciprocally altered E-Cadherin expression ($\textit{p}$ = <0.001) amongst other EMT markers. Immunohistochemistry of excised tumors 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 signaling 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 tumor dissemination of prostate cancer through alteration of EMT. Detection of downregulated 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.

Keywords: Sef, negative regulator, metastasis, prostate cancer, EMT

Sponsorship: Grant sponsor: Medical Research Council/The Prostate Cancer Charity Clinical Research Training Fellowship (S.H.); Grant number: G1001961; Grant sponsor: The Royal College of Surgeons Surgical Research Fellowship (S.H.), Addenbrooke’s Charitable Trust Oncology Research Fellowship (S.H.) and the University of Cambridge Raymond and Beverly Sackler Studentship (S.H.) DOI: 10.1002/ijc.30604.

Embargo Lift Date: 2100-01-01


External DOI: https://doi.org/10.1002/ijc.30604

This record's URL: https://www.repository.cam.ac.uk/handle/1810/262951

Rights: Attribution 4.0 International

Licence URL: http://creativecommons.org/licenses/by/4.0/

Autor: Hori, SWadhwa, KPisupati, VZecchini, VRamos-Montoya, AWarren, AYNeal, DEGnanapragasam, VJShow moreShow less

Fuente: https://www.repository.cam.ac.uk/handle/1810/262951


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