title: Loss of hSef promotes metastasis through upregulation of EMT in prostate cancer.
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 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 signaling 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 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.
authors.affiliation: Academic Urology Group, Department of Surgery, University of Cambridge, Cambridge, United Kingdom.|Uro-oncology Group, Cancer Research UK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hori
authors.affiliation: Academic Urology Group, Department of Surgery, University of Cambridge, Cambridge, United Kingdom.|Uro-oncology Group, Cancer Research UK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: Karan
authors.initials: K
authors.lastname: Wadhwa
authors.affiliation: Academic Urology Group, Department of Surgery, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Venkat
authors.initials: V
authors.lastname: Pisupati
authors.affiliation: Uro-oncology Group, Cancer Research UK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zecchini
authors.affiliation: Uro-oncology Group, Cancer Research UK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramos-Montoya
authors.affiliation: Department of Pathology, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Warren
authors.affiliation: Uro-oncology Group, Cancer Research UK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Academic Urology Group, Department of Surgery, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Gnanapragasam
mesh_terms: D000818:Animals; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D018123:Receptors, Interleukin / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; C477526:IL17RD protein, human; D018123:Receptors, Interleukin; D048051:p38 Mitogen-Activated Protein Kinases
keywords: EMT; Sef; metastasis; negative regulator; prostate cancer