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Effects of murine Oncostatin M on OP9 stromal cells and NIH/3T3 fibroblasts

ABSTRACT: The IL-6 cytokine Oncostatin M (OSM) is involved in cell development, growth, hematopoiesis, inflammation and cancer. Intriguingly, OSM has proliferative and antiproliferative effects de-pending on the target cell. The molecular mechanisms underlying these opposing effects are not fully understood and its role in tumorigenesis remains controversial. In the present study, we investigated the effect of murine OSM (mOSM) on proliferation in two cell types of distinct origin. We found that mOSM impairs the proliferation of murine bone marrow (BM) stromal cell lines and primary BM stromal cells, whereas murine fibroblasts responded to mOSM with increased proliferation. When we set out to reveal the mechanisms underlying these opposing effects of OSM on proliferation, we detected increased expression of the OSM receptors OSMR and LIFR in stromal cells. Interestingly, Osmr knockdown and Lifr overexpression attenuated the OSM-mediated effect on proliferation in both cell lines indicating that mOSM affected the pro-liferation of both cell lines signaling mainly through the OSMR. Furthermore, mOSM induced activation of the JAK-STAT, PI3K-AKT and MAPK-ERK pathways in OP9 and NIH/3T3 cells with differences in total protein levels between the two cell lines. Our findings offer new insights into the regulation of proliferation by mOSM.

ORGANISM(S): Mus musculus

PROVIDER: GSE185646 | GEO | 2021/10/13

REPOSITORIES: GEO

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Project description:For many oncogenes, increased expression resulting from copy number gain confers a selective advantage to cells that consequently make up the tumour bulk. To identify oncogenes of potential biological significance in cervical squamous cell carcinoma (SCC), 36 primary samples and ten cell lines were screened by array comparative genomic hybridization (CGH). The most commonly occurring regions of copy number gain that also showed amplification were 5p15.2–14.3 (59%), 5p13.3 (65%), and 5p13.2–13.1 (63%). Gene copy numbers were significantly associated with expression levels for three candidate oncogenes at these loci: OSMR (oncostatin M receptor) (p = 0.03), PDZK3 (PDZ domain containing protein 3) (p = 0.04), and TRIO (triple functional domain) (p = 0.03). Further examination by fluorescence in situ hybridization on a tissue microarray of 110 primary cervical SCC samples revealed copy number gain frequencies of 60.9%, 57.3%, and 54.5% for OSMR, PDZK3, and TRIO, respectively, with OSMR adversely influencing overall patient survival independently of tumour stage (p = 0.046). By array CGH, copy number gain of OSMR was not seen in any of 40 microdissected precursor cervical squamous intraepithelial lesions (SILs). Moreover, global mRNA expression analysis, using Affymetrix U133A 2.0 Arrays, showed no overexpression of OSMR in SILs, suggesting that OSMR gain and overexpression are relatively late steps in cervical carcinogenesis. In the cervical SCC cell lines CaSki and SW756, exogenous OSM activated downstream-signalling elements of OSMR including STAT3, p44/42 MAPK, and S6 ribosomal protein, and induced transcription of the angiogenic factor VEGF, effects that were reduced by OSMR depletion using RNA interference. We conclude that copy number gain of OSMR is frequently found in cervical SCC and is associated with adverse clinical outcome. As well as being a potential prognostic marker, OSMR is a candidate cell surface therapeutic target aCGH of high grade late stage primary cervical SCCs obtained from the archives of the Kidwai Memorial Institute of Oncology,

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Effects of murine Oncostatin M on OP9 stromal cells and NIH/3T3 fibroblasts

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