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Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells

Oncogene volume 22, pages 894–905 (2003)Cite this article

Abstract

A number of studies have demonstrated that the STAT pathway is an important signaling cascade utilized by the IL-6 cytokine family to regulate a variety of cell functions. However, the downstream target genes of STAT activation that mediate the cytokine-induced cellular responses are largely uncharacterized. The aims of the current study are to determine whether the STAT signaling pathway is critically involved in the oncostatin M (OM)-induced growth inhibition and morphological changes of MCF-7 cells and to identify STAT3-target genes that are utilized by OM to regulate cell growth and morphology. We show that expression of a dominant negative (DN) mutant of STAT3 in MCF-7 cells completely eliminated the antiproliferative activity of OM, whereas expression of DN STAT1 had no effect. The growth inhibition of breast cancer cells was achieved through a concerted action of OM on cell cycle components. We have identified four cell cycle regulators including c-myc, cyclin D1, c/EBPδ, and p53 as downstream effectors of the OM-activated STAT3 signaling cascade. The expression of these genes is differentially regulated by OM in MCF-7 cells, but is unaffected by OM in MCF-7-dnStat3 stable clones. We also demonstrate that the OM-induced morphological changes are correlated with increased cell motility in a STAT3-dependent manner. Expression analysis of extracellular matrix (ECM) proteins leads to the identification of fibronectin as a novel OM-regulated ECM component. Our studies further reveal that STAT3 plays a key role in the robust induction of fibronectin expression by OM in MCF-7 and T47D cells. These new findings provide a molecular basis for the mechanistic understanding of the effects of OM on cell growth and migration.

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Abbreviations

ECM:

extracellular matrix

EMSA:

electrophoretic mobility shift assay

ERK:

extracellular signal regulated kinase

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

IL-6:

interleukin-6

OM:

oncostatin M

STAT:

signal transducer and activator of transcription

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Acknowledgements

We thank Dr Shizuo Arika for providing us with the plasmid-pEF-dnStat3, Dr Xin-Yuan Fu for providing the plasmids pEFneo and pEFneo-dnStat1, Dr Richard Jove for providing the Stat3 reporter plasmid, and Dr Ali Badache for providing T47D-dnStat3 cell line. These reagents are key components for this investigation. This study was supported by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service), by Grant (1RO1CA83648-01) from the National Cancer Institute and by Grant (BC990960) from the United States Army Medical Research and Development Command.

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  1. Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, 94304, CA, USA

    Fang Zhang, Cong Li & Jingwen Liu

  2. Department of Neurology and Internal Medicine A (Oncology), Westfälische Wilhelms-Universität Münster, Münster, Germany

    Hartmut Halfter

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Correspondence to Jingwen Liu.

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Zhang, F., Li, C., Halfter, H. et al. Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells. Oncogene 22, 894–905 (2003). https://doi.org/10.1038/sj.onc.1206158

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