title: Overexpression of the oncostatin M receptor in cervical squamous cell carcinoma cells is associated with a pro-angiogenic phenotype and increased cell motility and invasiveness.
abstract: Oncostatin M receptor (OSMR) shows frequent copy number gain and overexpression in advanced cervical squamous cell carcinoma (SCC). We used cell-based in vitro assays, RNA interference, and integrative gene expression profiling to investigate the functional significance of this observation. CaSki and SW756 were selected as representative cervical SCC cells that overexpressed OSMR, and ME180 and MS751 as cells that did not. The STAT-dependent pro-angiogenic factors VEGF-A and ID1 were rapidly induced by OSM in CaSki/SW756 but not in ME180/MS751. However, rapid induction did occur in MS751 following forced OSMR overexpression, while depleting OSMR in CaSki abrogated VEGF-A expression. Conditioned medium from both CaSki and SW756 stimulated endothelial tube formation in vitro, effects that were inhibited by depleting OSMR in the SCC cells. For both CaSki and SW756, migration in a wound healing assay and invasion through Matrigel were stimulated by OSM and consistently inhibited by OSMR depletion. The phenotype was rescued by transfection with OSMR containing a silent mutation that provided specific siRNA resistance. Overall, there was a positive correlation between OSMR levels and invasiveness. We used gene expression profiling to identify genes induced by OSM in CaSki/SW756 but not in ME180/MS751. The most prominent gene ontology category groups for the differentially expressed genes were cell motility/invasion, angiogenesis, signal transduction, and apoptosis. We also profiled 23 cervical SCC samples, identifying genes that were differentially expressed in cases with OSMR overexpression versus those without. Integration of the datasets identified 15 genes that showed consistent differential expression in association with OSMR levels in vitro and in vivo. We conclude that OSMR overexpression in cervical SCC cells provides increased sensitivity to OSM, which induces pro-malignant changes. OSMR is a potential prognostic and therapeutic target in cervical SCC. The genes that mediate OSM:OSMR effects will be valuable indicators of the effectiveness of antibody blockade in pre-clinical systems.
authors.affiliation: Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge, CB2 0XZ, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Winder
authors.forename: Anasuya
authors.initials: A
authors.lastname: Chattopadhyay
authors.forename: Balaji
authors.initials: B
authors.lastname: Muralidhar
authors.forename: Julien
authors.initials: J
authors.lastname: Bauer
authors.forename: William R
authors.initials: WR
authors.lastname: English
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.forename: Konstantina
authors.initials: K
authors.lastname: Karagavriilidou
authors.forename: Ian
authors.initials: I
authors.lastname: Roberts
authors.forename: Mark R
authors.initials: MR
authors.lastname: Pett
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.forename: Nicholas
authors.initials: N
authors.lastname: Coleman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D053683:Oncostatin M / Q000494:pharmacology; D053681:Oncostatin M Receptor beta Subunit / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C508348:OSMR protein, human; D053681:Oncostatin M Receptor beta Subunit; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D053683:Oncostatin M