Coexpression of oncostatin M and its receptors and evidence for STAT3 activation in human ovarian carcinomas.
The expression of oncostatin M and leukemia inhibitory factor (LIF), JAK-STAT activators and members of the interleukin-6 family of cytokines, were examined in a series of primary ovarian carcinomas using immunohistochemistry. The malignant epithelial cells of all 29 ovarian carcinomas examined expressed oncostatin M; none expressed LIF. Oncostatin M can activate two related receptors, one consisting of a low-affinity LIF receptor subunit, LIFR beta, which forms a heterocomplex with the gp130 signal transducing protein and can recognize both oncostatin M and LIF, and a second heterocomplex consisting of a subunit that specifically recognizes oncostatin M, OSMR beta, and the gp130 protein. By immunohistochemistry, 25 of 25 ovarian carcinomas examined expressed the LIFR beta subunit in the malignant epithelial cells (all samples express gp130), and two-thirds the ovarian carcinomas studied expressed OSMR beta mRNA as determined by RT-PCR. Thus oncostatin M and its receptors are commonly coexpressed in malignant ovarian epithelial cells, and represent a potential autocrine loop in this tumor type. STAT3, of one the signaling proteins downstream of the oncostatin M/LIF receptors, was found in its phosphorylated, activated form (phosphotyrosine 705 STAT3) in the malignant epithelial cells of 17 of 23 ovarian carcinomas examined (74%) as determined by immunohistochemistry; this suggests that this protein is constitutively activated in most ovarian carcinomas, as it is in many other human malignancies. Recombinant human Oncostatin M (rhOSM) can induce the transient tyrosine 705 phosphorylation of STAT3 in serum-starved LIFR beta/OSMR beta expressing ovarian carcinoma cell lines, but does not alter cell growth and effects only a modest increase in the apoptotic rate in these cultured cells. Oncostatin M and its receptors may be part of a network of cytokine systems within ovarian carcinomas that may act to maintain STAT3 in its activated form, a phenomenon associated with the malignant phenotype.
Savarese
Todd M
TM
Cytokine/Cytokine Receptor LINK Laboratory, Cancer Center, University of Massachusetts Medical School, Worcester, 01655, USA. Todd.Savarese@umassmed.edu
Campbell
Cara L
CL
McQuain
Catherine
C
Mitchell
Kathryn
K
Guardiani
Rachel
R
Quesenberry
Peter J
PJ
Nelson
Beth E
BE
D000209:Acute-Phase Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D017209:Apoptosis; D001483:Base Sequence; D002277:Carcinoma / Q000145:classification / Q000235:genetics / Q000473:pathology; D016923:Cell Death; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D009367:Neoplasm Staging; D053683:Oncostatin M; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010446:Peptide Fragments; D010455:Peptides / Q000235:genetics*; D019000:Phosphotyrosine / Q000032:analysis; D018121:Receptors, Cytokine / Q000235:genetics*; D053677:Receptors, Oncostatin M; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; C508351:OSM protein, human; D010446:Peptide Fragments; D010455:Peptides; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D053683:Oncostatin M; D019000:Phosphotyrosine