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.

Oncostatin M treatment increases the responsiveness toward cisplatin‑based chemoradiotherapy in cervical cancer cells in a STAT3‑dependent manner

“…Recent studies indicate that OSM-R is overexpressed in advanced cervical squamous cell carcinomas making the cells susceptible for OSM signals. However, high expression of OSM-R in cervical cancers is associated with worse clinical outcome and OSM signals were described to initiate several pro-tumorigenic effects (37,38). For this reason, OSM-R is recommended as a candidate for antibody-mediated inhibition to block pro-malignant effects (38,39).…”

Stat3-coordinated Lin-28–let-7–HMGA2 and miR-200–ZEB1 circuits initiate and maintain oncostatin M-driven epithelial–mesenchymal transition

“…High expression of the OSM receptor in cervical squamous cell carcinoma cells has been associated with increased cell motility and invasiveness, implicating a potential role of OSM in tumor progression. 35 However, the effect of OSM on EMT in human cancer cells in vivo has not been explored. 36 In this study, we show that the autocrine/paracrine signaling of OSM by tumor and inflammatory cells, particularly macrophages, closely correlated with invasive characteristics of human breast cancers, that OSM stimulation was sufficient to induce EMT not only in vitro but also in vivo and that OSM promoted spontaneous lung metastases in MCF-7 breast cancer xenograft mouse model.…”

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

“…1,[19][20][21][22][23][24]28,33,74,[87][88][89][90][91][92][93] For example, in addition to the increased OSM levels in the breast TME, breast cancer cells also display elevated OSMR expression levels, which is associated with adverse clinical outcomes. 32,71,83,88,92,94 Notably, the more aggressive basal-like or triple-negative breast cancer subtype expresses markedly higher levels of OSMR when compare with the less aggressive luminal subtype. 71 Moreover, elevated OSMR expression correlates with increased expression of the cancer stem cell (CSC) marker CD44.…”