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

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 an...

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Published in:The Journal of pathology 2011-11, Vol.225 (3), p.448-462
Main Authors: Winder, David M, Chattopadhyay, Anasuya, Muralidhar, Balaji, Bauer, Julien, English, William R, Zhang, Xiao, Karagavriilidou, Konstantina, Roberts, Ian, Pett, Mark R, Murphy, Gillian, Coleman, Nicholas
Format: Article
Language:English
Subjects:
angiogenesis
Antineoplastic Agents - pharmacology
Biological and medical sciences
Biomarkers, Tumor - biosynthesis
Biomarkers, Tumor - genetics
Carcinoma, Squamous Cell - blood supply
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - metabolism
Carcinoma, Squamous Cell - pathology
cell migration
Cell Movement - drug effects
Cell Proliferation
cervix
Dermatology
Female
Female genital diseases
gene expression
Gene Expression Profiling - methods
Gene Expression Regulation, Neoplastic - drug effects
Gynecology. Andrology. Obstetrics
Humans
invasion
Investigative techniques, diagnostic techniques (general aspects)
Medical sciences
Neoplasm Invasiveness
Neoplasm Proteins - biosynthesis
Neoplasm Proteins - genetics
Neoplastic Stem Cells - pathology
Neovascularization, Pathologic - genetics
Neovascularization, Pathologic - metabolism
Oligonucleotide Array Sequence Analysis - methods
oncostatin M
Oncostatin M - pharmacology
oncostatin M receptor
Oncostatin M Receptor beta Subunit - biosynthesis
Oncostatin M Receptor beta Subunit - genetics
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
RNA, Neoplasm - genetics
RNA, Small Interfering - genetics
Signal Transduction - drug effects
squamous cell carcinoma
Tumor Cells, Cultured
Tumors
Tumors of the skin and soft tissue. Premalignant lesions
Uterine Cervical Neoplasms - blood supply
Uterine Cervical Neoplasms - genetics
Uterine Cervical Neoplasms - metabolism
Uterine Cervical Neoplasms - pathology
Vascular Endothelial Growth Factor A - metabolism
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Summary: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. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
ISSN:0022-3417
1096-9896
DOI:10.1002/path.2968