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Signal Transducer and Activator of Transcription 1 (STAT1) Knock-down Induces Apoptosis in Malignant Pleural Mesothelioma

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Pathology & Oncology Research

Abstract

Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura. Its incidence is still increasing in Europe and the prognosis remains poor. We investigated the oncogenic function of signal transducer and activator of transcription 1 (STAT1) in MPM in more detail. A miRNA profiling was performed on 52 MPM tissue samples. Upregulated miRNAs (targeting SOCS1/3) were knocked-down using miRNA inhibitors. mRNA expression levels of STAT1/3, SOCS1/3 were detected in MPM cell lines. STAT1 has been knocked-down using siRNA and qPCR was used to detect mRNA expression levels of all JAK/STAT family members and genes that regulate them. An immunohistochemical staining was performed to detect the expression of caspases. STAT1 was upregulated and STAT3 was downregulated, SOCS1/3 protein was not detected but it was possible to detect SOCS1/3 mRNA in MPM cell lines. The upregulated miRNAs were successfully knocked-down, however the expected effect on SOCS1 expression was not detected. STAT1 knock-down had different effects on STAT3/5 expression. Caspase 3a and 8 expression was found to be increased after STAT1 knock-down. The physiologic regulation of STAT1 via SOCS1 is completely lost in MPM and it does not seem that the miRNAs identified by now, do inhibit the expression of SOCS1. MPM cell lines compensate STAT1 knock-down by increasing the expression of STAT3 or STAT5a, two genes which are generally considered to be oncogenes. And much more important, STAT1 knock-down induces apoptosis in MPM cell lines and STAT1 might therefore be a target for therapeutic intervention.

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Acknowledgements

We gratefully thank Hildegard Gleixner, Virginia Brenner, Elisabeth Grygar and Mohammed Al-Effah, Institute of Pathology, Medical University of Graz, Karin Wagner and Theresa Maierhofer, Center for Medical Research, Medical University of Graz, Franz Quehenberger, Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz as well as Thomas Mauthner, Institute for Computer Graphics and Vision, Graz University of Technology for excellent technical assistance.

The study was supported by an unrestricted grant from Pfizer Austria.

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Authors and Affiliations

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

    Lisa Arzt, Iris Halbwedl & Helmut H. Popper

  2. Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, A-8036, Graz, Austria

    Margit Gogg-Kamerer

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  1. Lisa Arzt
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Correspondence to Lisa Arzt.

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Arzt, L., Halbwedl, I., Gogg-Kamerer, M. et al. Signal Transducer and Activator of Transcription 1 (STAT1) Knock-down Induces Apoptosis in Malignant Pleural Mesothelioma. Pathol. Oncol. Res. 23, 595–605 (2017). https://doi.org/10.1007/s12253-016-0157-3

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