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

Our plain-English summary of Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma, by L. Arzt, H. Kothmaier, I. Halbwedl, et al (Virchows Archiv, 2014).

The study

• Authors: L. Arzt, H. Kothmaier, I. Halbwedl, F. Quehenberger, H.H. Popper
• Journal: Virchows Archiv
• Published: 2014;465(1):79-88
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This laboratory study, from the Medical University of Graz, Austria, examined STAT1, a protein involved in signals that control cell survival, in malignant pleural mesothelioma. The authors tested six mesothelioma cell lines, some treated with the immune signal interferon-gamma. They also tested 16 epithelioid tumor samples from patients who died within 2 years of diagnosis. The study did not measure asbestos exposure. In all six cell lines, STAT1 was higher than a related protein, STAT3, and STAT1's regulator SOCS1 was absent. Interferon-gamma did not change STAT1 levels but increased one activated form (phosphorylated at tyrosine 701) within 15 minutes. All 16 tumor samples showed high STAT1. The tyrosine 701 form was significantly higher than the serine 727 form: p=0.00036 by protein microarray and p=0.03426 by tissue staining. SOCS1 was not detected in the tumors but was seen in infiltrating inflammatory cells. The authors concluded that STAT1 most likely acts like an oncogene in this disease and that blocking it may offer a treatment approach. They said other regulators still need study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of mesothelioma cell lines and of preserved human tumor tissue samples
• Who was studied: Six mesothelioma cell lines (CRL-5915, MSTO-211H, Hmeso, PPM Mill, PPM Gar, PPM Rob), plus HepG2 cells as a control. Also 16 surgically resected epithelioid malignant pleural mesothelioma cases from short-time survivors (death within 2 years from diagnosis), studied with approval of the Medical University of Graz Ethics Committee
• Exposure: No asbestos exposure was studied. The cell lines were treated in the laboratory with 50 ng/ml interferon-gamma for 15 minutes, 1 hour and 4 hours
• Main results:
  • In all six mesothelioma cell lines, STAT1 expression was higher than STAT3 expression
  • SOCS1 was absent in the mesothelioma cell lines but detected in the HepG2 control cell line
  • In the cell lines, interferon-gamma did not change STAT1, STAT3 or SOCS1 expression, but STAT1 phosphorylated on tyrosine 701 increased as early as 15 minutes after treatment
  • STAT1 phosphorylated on serine 727 was not detected in the cell lines, whether treated or untreated
  • In the tumor tissue samples, STAT1 was highly expressed in 16 of 16 cases
  • In the tumor tissue samples, STAT1 phosphorylation at tyrosine 701 was significantly higher than at serine 727 (protein array p=0.00036; immunohistochemistry p=0.03426)
  • SOCS1 was undetectable in the tumor tissue (p=0.00011) but was expressed in infiltrating inflammatory cells
• The authors' conclusion: The authors concluded that STAT1 and phosphorylated STAT1 most likely act like an oncogene in malignant pleural mesothelioma by activating antiapoptotic molecules, and that targeting this signaling by STAT1 inhibition may provide a novel therapeutic approach
• Limitations the authors state:
  • The authors assumed that Western Blot was not sensitive enough to detect the phosphorylated forms in the cell line samples, which would explain why the cell lines differed from the tissue samples
  • The authors stated that further experiments are needed to clarify whether sustained STAT1 activity is caused only by the lack of SOCS1 or also by other negative regulators

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pleura, Prognosis, Epithelioid, Mesothelioma, Cytokine, Immunohistochemistry, Chemotherapy.

Related studies

• Signal Transducer and Activator of Transcription 1 (STAT1) Knock-down Induces Apoptosis in Malignant Pleural Mesothelioma — L. Arzt, I. Halbwedl, et al. (2017)
• Cul4A is an oncogene in malignant pleural mesothelioma — M.S. Hung, J.H. Mao, et al. (2011)
• Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling — G.J. Gordon, G.N. Rockwell, et al. (2005)
• Loss of NF2 Induces TGFβ Receptor 1-mediated Noncanonical and Oncogenic TGFβ Signaling: Implication of the Therapeutic Effect of TGFβ Receptor 1 Inhibitor on NF2 Syndrome — J.H. Cho, A.Y. Oh, et al. (2018)
• Oncogenes and tumor-suppressor genes in mesothelioma--a synopsis — J.F. Lechner, J. Tesfaigzi, et al. (1997)
• Tumorigenicity of human mesothelial cell line transfected with EJ-ras oncogene — R.R. Reddel, L. Malan-Shibley, et al. (1989)

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