Gain and overexpression of the oncostatin M receptor occur frequently in cervical squamous cell carcinoma and are associated with adverse clinical outcome

Abstract

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.

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.…”

c-MYC Functions as a Molecular Switch to Alter the Response of Human Mammary Epithelial Cells to Oncostatin M

“…Second, OSM-positive macrophages are predominantly localized at the advancing, infiltrative margins of carcinomas, which may implicate OSM in tumor invasion (36). Third, in addition to OSM in the tumor microenvironment, the OSM receptor (OSMR) is also frequently overexpressed in cervical and ovarian carcinomas, and is associated with adverse clinical outcome (37, 38). Finally, the widely used chemotherapy drug cisplatin induces peritoneal and bone marrow-derived macrophages to induce significant OSM secretion (39, 40).…”

CLDN1 expression in cervical cancer cells is related to tumor invasion and metastasis

“…However, cervical cancer remains the third most commonly diagnosed malignancy and the fourth leading cause of cancer death in females worldwide [1]. Persistent infection with high-risk human papillomavirus (HPV) is recognized as a necessary initiating event but not a sufficient event in cervical carcinogenesis [2]. The integration of HPV into the human genome is recognized as an important basis for cervical carcinogenesis [3].…”