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

Our plain-English summary of Signal Transducer and Activator of Transcription 1 (STAT1) Knock-down Induces Apoptosis in Malignant Pleural Mesothelioma, by L. Arzt, I. Halbwedl, M. Gogg-Kamerer, et al (Pathology Oncology Research, 2017).

The study

• Authors: L. Arzt, I. Halbwedl, M. Gogg-Kamerer, H.H. Popper
• Journal: Pathology Oncology Research
• Published: 2017;23(3):595-605
• Cited by: 5 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 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.

In plain English

This laboratory study of malignant pleural mesothelioma did not examine asbestos exposure. It used 52 surgically removed epitheloid tumor samples and six mesothelioma cell lines. The authors asked why SOCS1, which normally switches off the signaling protein STAT1, is missing in this cancer, and what reducing STAT1 does. In tumor samples, STAT1 was expressed much more strongly than STAT3; SOCS1 and SOCS3 proteins were not detected. Three microRNAs predicted to act on SOCS1 and SOCS3 (miR-19b, miR-30b, miR-30c) were measured in 45 of the 52 samples and were raised in nearly all of them. Cell lines had detectable SOCS messenger RNA but no SOCS protein. Blocking the microRNAs in one cell line, CRL-5915, did not change SOCS1 protein. Reducing STAT1 in three cell lines raised STAT3 slightly in two and STAT5a in one. Treated cells stained for caspase 8 (100% of cells) and, more weakly, caspase 3a, which the authors read as a sign of apoptosis (cell death). The authors concluded that STAT1 acts like an oncogene in this disease and, with STAT3 and STAT5a, may be a treatment target.

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 using human tumor tissue samples and mesothelioma cell lines (microRNA profiling, immunohistochemistry, microRNA inhibition and STAT1 knock-down experiments)
• Who was studied: 52 epitheloid malignant pleural mesothelioma tumor samples from surgery (open biopsies or pleurectomies), with ethics approval from the Medical University of Graz, Austria. Also six mesothelioma cell lines (CRL-5915, MSTO-211H, Hmeso, PPM Mill, PPM Gar, PPM Rob) and the HepG2 cell line as a control.
• Main results:
  • In tumor tissue samples, STAT1 was much more highly expressed than STAT3. SOCS1 and SOCS3 proteins were not detected by immunohistochemistry.
  • Profiling identified 29 microRNAs that were up- or downregulated. The microRNAs targeting SOCS1 and SOCS3 were measured individually in 45 of the 52 tumor samples. miR-19b, miR-30b and miR-30c were upregulated in nearly all samples (data not shown).
  • In the mesothelioma cell lines, SOCS messenger RNA was detectable but SOCS protein was not.
  • In the CRL-5915 cell line, the only one used for this experiment, blocking the microRNAs singly or in combination did not change SOCS1 protein expression.
  • After STAT1 knock-down, CRL-5915 cells showed upregulation of STAT5a, while MSTO-211H and Hmeso cells showed slightly upregulated STAT3.
  • Three genes changed in the same direction in all three cell lines after STAT1 knock-down: F2R was downregulated, and JUNB and CDKN1A were upregulated.
  • Caspase 3a and caspase 8 staining was found in STAT1 knock-down samples but not in control samples. All cells (100%) stained positive for caspase 8, while caspase 3a staining was mild and not seen in all cells.
• The authors' conclusion: The authors concluded that their results support earlier findings that STAT1 acts like an oncogene in malignant pleural mesothelioma. They wrote that the results provide first evidence that STAT1, together with STAT3 and STAT5a, could be a therapeutic target.
• Limitations the authors state:
  • The authors suggested the STAT1 knock-down may have lasted too short a time to start the whole apoptotic program.
  • No cell growth inhibition was seen under the microscope after STAT1 knock-down.
  • Blocking the microRNAs did not affect SOCS1 expression in the mesothelioma cell lines.
  • The control cell line HepG2 showed similar microRNA and SOCS patterns yet expresses SOCS1 protein, so the identified microRNAs did not influence SOCS expression in that cell line.

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: Apoptosis, Pleural Mesothelioma, Pleura, Prognosis, Immunohistochemistry.

Related studies

• Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma — L. Arzt, H. Kothmaier, et al. (2014)
• Resveratrol and clofarabine induces a preferential apoptosis-activating effect on malignant mesothelioma cells by Mcl-1 down-regulation and caspase-3 activation — Y.J. Lee, Y.J. Lee, et al. (2015)
• Licochalcone A induces apoptosis in malignant pleural mesothelioma through downregulation of Sp1 and subsequent activation of mitochondria-related apoptotic pathway — K.H. Kim, G. Yoon, et al. (2015)
• Inhibition of NADPH oxidase 4 induces apoptosis in malignant mesothelioma: Role of reactive oxygen species — M. Tanaka, Y. Miura, et al. (2015)
• Phosphatidylinositol Induces Caspase-Independent Apoptosis of Malignant Pleural Mesothelioma Cells by Accumulating AIF in the Nucleus — S. Kanemura, A. Tsuchiya, et al. (2015)
• Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro — M. You, J. Varona-Santos, et al. (2014)

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