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Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma

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Abstract

Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura. Its incidence is increasing in Europe and the prognosis remains poor. We compared epithelioid MPM in short and long survivors, and identified signal transducer and activator of transcription 1 (STAT1) as probably being responsible for antiapoptotic signaling and chemoresistance. Six mesothelioma cell lines were evaluated by Western Blot. We also analyzed 16 epithelioid MPM tissue samples for the phosphorylation status of STAT1 and the expression of its negative regulator, the suppressor of cytokine signaling 1 (SOCS1). Formalin-fixed and paraffin-embedded tissue specimens were evaluated by protein-lysate microarray and immunohistochemistry. We found STAT1 to be highly expressed and STAT3 downregulated in MPM cell lines. The expression of STAT1 phosphorylated on tyrosine 701 (Y701) was increased by interferon-gamma (IFN-γ) treatment, whereas SOCS1 was not expressed. The expression of STAT1 phosphorylated on serine 727 (S727) was not detected in mesothelioma cell lines and was not stimulated by IFN-γ. STAT1 was phosphorylated on tyrosine 701 and serine 727 in MPM tissue samples. The expression of pSTAT1-Y701 was increased compared to pSTAT1-S727. SOCS1 was again not detectable. STAT1 is upregulated in MPM, and its action may be prolonged by a loss of the negative regulator SOCS1. STAT1 might, therefore, be a target for therapeutic intervention, with the intention to restore apoptotic mechanisms and sensitivity to chemotherapy. However, other regulatory mechanisms need to be investigated to clarify if lack of expression of SOCS1 is the only reason for sustained STAT1 expression in MPM.

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Acknowledgments

This study is partly supported by the Styrian Cancer Aid Society and by an unrestricted grant from Pfizer Austria. We gratefully thank Hildegard Gleixner, Margit Gogg-Kamerer, Elisabeth Grygar, Mohammed Al-Effah, and Ralph König, Institute of Pathology, Medical University of Graz, for their excellent technical assistance.

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All authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Institute of Pathology, Research Unit for Molecular Lung- and Pleurapathology, Medical University of Graz, Auenbruggerplatz 25, 8036, Graz, Austria

    Lisa Arzt, Hannelore Kothmaier, Iris Halbwedl & Helmut H. Popper

  2. Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Auenbruggerplatz 2/V, 8036, Graz, Austria

    Franz Quehenberger

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  1. Lisa Arzt
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Arzt, L., Kothmaier, H., Halbwedl, I. et al. Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma. Virchows Arch 465, 79–88 (2014). https://doi.org/10.1007/s00428-014-1584-8

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