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Virchows Archiv

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01.07.2014 | Original Article

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

verfasst von: Lisa Arzt, Hannelore Kothmaier, Iris Halbwedl, Franz Quehenberger, Helmut H. Popper

Erschienen in: Virchows Archiv | Ausgabe 1/2014

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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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Vogelzang NJ, Porta C, Mutti L (2005) New agents in the management of advanced mesothelioma. Semin Oncol 32(3):336–350PubMedCrossRef

Shukla A, Bosenberg MW, MacPherson MB, Butnor KJ, Heintz NH, Pass HI, Carbone M, Testa JR, Mossman BT (2009) Activated cAMP response element binding protein is overexpressed in human mesotheliomas and inhibits apoptosis. Am J Pathol 175(5):2197–2206. doi:10.2353/ajpath.2009.090400 PubMedCentralPubMedCrossRef

Ramos-Nino ME, Testa JR, Altomare DA, Pass HI, Carbone M, Bocchetta M, Mossman BT (2006) Cellular and molecular parameters of mesothelioma. J Cell Biochem 98(4):723–734. doi:10.1002/jcb.20828 PubMedCentralPubMedCrossRef

Nowak AK, Lake RA, Kindler HL, Robinson BW (2002) New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents. Semin Oncol 29(1):82–96PubMedCrossRef

Boutin C, Nussbaum E, Monnet I, Bignon J, Vanderschueren R, Guerin JC, Menard O, Mignot P, Dabouis G, Douillard JY (1994) Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer 74(9):2460–2467PubMedCrossRef

Hand A, Pelin K, Mattson K, Linnainmaa K (1995) Interferon (IFN)-alpha and IFN-gamma in combination with methotrexate: in vitro sensitivity studies in four human mesothelioma cell lines. Anticancer Drugs 6(1):77–82PubMedCrossRef

Hand AM, Husgafvel-Pursiainen K, Pelin K, Vallas M, Suitiala T, Ekman A, Mattson M, Mattson K, Linnainmaa K (1992) Interferon-alpha and -gamma in combination with chemotherapeutic drugs: in vitro sensitivity studies in four human mesothelioma cell lines. Anticancer Drugs 3(6):687–694PubMedCrossRef

Hand AM, Husgafvel-Pursiainen K, Tammilehto L, Mattson K, Linnainmaa K (1991) Malignant mesothelioma: the antiproliferative effect of cytokine combinations on three human mesothelioma cell lines. Cancer Lett 58(3):205–210PubMedCrossRef

Phan-Bich L, Buard A, Petit JF, Zeng L, Tenu JP, Chretien P, Monnet I, Boutin C, Bignon J, Lemaire G, Jaurand MC (1997) Differential responsiveness of human and rat mesothelioma cell lines to recombinant interferon-gamma. Am J Respir Cell Mol Biol 16(2):178–186. doi:10.1165/ajrcmb.16.2.9032125 PubMedCrossRef

10.

Zeng L, Buard A, Monnet I, Boutin C, Fleury J, Saint-Etienne L, Brochard P, Bignon J, Jaurand MC (1993) In vitro effects of recombinant human interferon gamma on human mesothelioma cell lines. Int J Cancer 55(3):515–520PubMedCrossRef

11.

Buard A, Vivo C, Monnet I, Boutin C, Pilatte Y, Jaurand MC (1998) Human malignant mesothelioma cell growth: activation of janus kinase 2 and signal transducer and activator of transcription 1alpha for inhibition by interferon-gamma. Cancer Res 58(4):840–847PubMed

12.

Rawlings JS, Rosler KM, Harrison DA (2004) The JAK/STAT signaling pathway. J Cell Sci 117(Pt 8):1281–1283. doi:10.1242/jcs.00963 PubMedCrossRef

13.

Calo V, Migliavacca M, Bazan V, Macaluso M, Buscemi M, Gebbia N, Russo A (2003) STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol 197(2):157–168. doi:10.1002/jcp.10364 PubMedCrossRef

14.

Reich NC, Liu L (2006) Tracking STAT nuclear traffic. Nat Rev Immunol 6(8):602–612. doi:10.1038/nri1885 PubMedCrossRef

15.

Sadzak I, Schiff M, Gattermeier I, Glinitzer R, Sauer I, Saalmuller A, Yang E, Schaljo B, Kovarik P (2008) Recruitment of Stat1 to chromatin is required for interferon-induced serine phosphorylation of Stat1 transactivation domain. Proc Natl Acad Sci USA 105(26):8944–8949. doi:10.1073/pnas.0801794105 PubMedCentralPubMedCrossRef

16.

Stephanou A, Latchman DS (2005) Opposing actions of STAT-1 and STAT-3. Growth Factors 23(3):177–182. doi:10.1080/08977190500178745 PubMedCrossRef

17.

Kothmaier H, Quehenberger F, Halbwedl I, Morbini P, Demirag F, Zeren H, Comin CE, Murer B, Cagle PT, Attanoos R, Gibbs AR, Galateau-Salle F, Popper HH (2008) EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors. Thorax 63(4):345–351. doi:10.1136/thx.2007.085241 PubMedCrossRef

18.

Buettner R, Mora LB, Jove R (2002) Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8(4):945–954PubMed

19.

Wormald S, Hilton DJ (2004) Inhibitors of cytokine signal transduction. J Biol Chem 279(2):821–824. doi:10.1074/jbc.R300030200 PubMedCrossRef

20.

Espert L, Dusanter-Fourt I, Chelbi-Alix MK (2005) Negative regulation of the JAK/STAT: pathway implication in tumorigenesis. Bull Cancer 92(10):845–857PubMed

21.

Klampfer L (2008) The role of signal transducers and activators of transcription in colon cancer. Front Biosci 13:2888–2899PubMedCrossRef

22.

Pass HI, Stevens EJ, Oie H, Tsokos MG, Abati AD, Fetsch PA, Mew DJ, Pogrebniak HW, Matthews WJ (1995) Characteristics of nine newly derived mesothelioma cell lines. Ann Thorac Surg 59(4):835–844PubMedCrossRef

23.

Reale FR, Griffin TW, Compton JM, Graham S, Townes PL, Bogden A (1987) Characterization of a human malignant mesothelioma cell line (H-MESO-1): a biphasic solid and ascitic tumor model. Cancer Res 47(12):3199–3205PubMed

24.

Shukla A, Hillegass JM, MacPherson MB, Beuschel SL, Vacek PM, Pass HI, Carbone M, Testa JR, Mossman BT (2010) Blocking of ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin. Mol Cancer 9:314. doi:10.1186/1476-4598-9-314 PubMedCentralPubMedCrossRef

25.

Ordonez NG (2007) What are the current best immunohistochemical markers for the diagnosis of epithelioid mesothelioma? A review and update. Hum Pathol 38(1):1–16PubMedCrossRef

26.

Becker KF, Schott C, Hipp S, Metzger V, Porschewski P, Beck R, Nahrig J, Becker I, Hofler H (2007) Quantitative protein analysis from formalin-fixed tissues: implications for translational clinical research and nanoscale molecular diagnosis. J Pathol 211(3):370–378PubMedCrossRef

27.

Kothmaier H, Rohrer D, Stacher E, Quehenberger F, Becker KF, Popper HH (2011) Comparison of formalin-free tissue fixatives: a proteomic study testing their application for routine pathology and research. Arch Pathol Lab Med 135(6):744–752PubMed

28.

Shaffer J (1986) Modified sequentially rejective multiple test procudures. J Am Stat Assoc 81(395):826–831CrossRef

29.

Arzt L, Kothmaier H, Quehenberger F, Halbwedl I, Popper HH (2011) STAT signalling in malignant mesothelioma: is there a regulatory effect of microRNAs? Mag Eur Med Oncol 4(1):38–42CrossRef

30.

Ma J, Cao X (2006) Regulation of Stat3 nuclear import by importin alpha5 and importin alpha7 via two different functional sequence elements. Cell Signal 18(8):1117–1126PubMedCrossRef

31.

Wenta N, Strauss H, Meyer S, Vinkemeier U (2008) Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations. Proc Natl Acad Sci USA 105(27):9238–9243PubMedCentralPubMedCrossRef

32.

McBride KM, Banninger G, McDonald C, Reich NC (2002) Regulated nuclear import of the STAT1 transcription factor by direct binding of importin-alpha. Embo J 21(7):1754–1763PubMedCentralPubMedCrossRef

33.

Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR (1997) Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 278(5343):1630–1632PubMedCrossRef

34.

Mita AC, Mita MM, Nawrocki ST, Giles FJ (2008) Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res 14(16):5000–5005. doi:10.1158/1078-0432.ccr-08-0746 PubMedCrossRef

35.

Kanwar RK, Cheung CH, Chang JY, Kanwar JR (2010) Recent advances in anti-survivin treatments for cancer. Curr Med Chem 17(15):1509–1515PubMedCrossRef

36.

Zimmerman M, Yang D, Hu X, Liu F, Singh N, Browning D, Ganapathy V, Chandler P, Choubey D, Abrams SI, Liu K (2010) IFN-gamma upregulates survivin and Ifi202 expression to induce survival and proliferation of tumor-specific T cells. PLoS One 5(11):e14076. doi:10.1371/journal.pone.0014076 PubMedCentralPubMedCrossRef

37.

Berishaj M, Gao SP, Ahmed S, Leslie K, Al-Ahmadie H, Gerald WL, Bornmann W, Bromberg JF (2007) Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer. Breast Cancer Res 9(3):R32. doi:10.1186/bcr1680 PubMedCentralPubMedCrossRef

38.

Braun DA, Fribourg M, Sealfon SC (2013) Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J Biol Chem 288(5):2986–2993. doi:10.1074/jbc.M112.386573 PubMedCentralPubMedCrossRef

39.

Russell MA, Cooper AC, Dhayal S, Morgan NG (2013) Differential effects of interleukin-13 and interleukin-6 on Jak/STAT signaling and cell viability in pancreatic beta-cells. Islets 5 (2)

40.

Yang X, Liang L, Zhang XF, Jia HL, Qin Y, Zhu XC, Gao XM, Qiao P, Zheng Y, Sheng YY, Wei JW, Zhou HJ, Ren N, Ye QH, Dong QZ, Qin LX (2013) MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting IL-6-Stat3 pathway. Hepatology. doi:10.1002/hep.26305

41.

Bromberg J (2002) Stat proteins and oncogenesis. J Clin Invest 109(9):1139–1142. doi:10.1172/jci15617 PubMedCentralPubMedCrossRef

42.

Aoki Y, Feldman GM, Tosato G (2003) Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 101(4):1535–1542. doi:10.1182/blood-2002-07-2130 PubMedCrossRef

43.

Qing Y, Stark GR (2004) Alternative activation of STAT1 and STAT3 in response to interferon-gamma. J Biol Chem 279(40):41679–41685. doi:10.1074/jbc.M406413200 PubMedCrossRef

44.

Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282(28):20059–20063. doi:10.1074/jbc.R700016200 PubMedCrossRef

45.

Liao J, Fu Y, Shuai K (2000) Distinct roles of the NH2- and COOH-terminal domains of the protein inhibitor of activated signal transducer and activator of transcription (STAT) 1 (PIAS1) in cytokine-induced PIAS1-Stat1 interaction. Proc Natl Acad Sci USA 97(10):5267–5272PubMedCentralPubMedCrossRef

46.

Ungureanu D, Vanhatupa S, Kotaja N, Yang J, Aittomaki S, Janne OA, Palvimo JJ, Silvennoinen O (2003) PIAS proteins promote SUMO-1 conjugation to STAT1. Blood 102(9):3311–3313. doi:10.1182/blood-2002-12-3816 PubMedCrossRef

47.

Lee JH, Park SM, Kim OS, Lee CS, Woo JH, Park SJ, Joe EH, Jou I (2009) Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes. Mol Cell 35(6):806–817. doi:10.1016/j.molcel.2009.07.021 PubMedCrossRef

48.

Madonna S, Scarponi C, De Pita O, Albanesi C (2008) Suppressor of cytokine signaling 1 inhibits IFN-gamma inflammatory signaling in human keratinocytes by sustaining ERK1/2 activation. FASEB J 22(9):3287–3297PubMedCrossRef

49.

Lesinski GB, Zimmerer JM, Kreiner M, Trefry J, Bill MA, Young GS, Becknell B, Carson WE 3rd (2010) Modulation of SOCS protein expression influences the interferon responsiveness of human melanoma cells. BMC Cancer 10:142. doi:10.1186/1471-2407-10-142 PubMedCentralPubMedCrossRef

50.

Klampfer L (2006) Signal transducers and activators of transcription (STATs): novel targets of chemopreventive and chemotherapeutic drugs. Curr Cancer Drug Targets 6(2):107–121PubMedCrossRef

51.

Iwahori K, Serada S, Fujimoto M, Ripley B, Nomura S, Mizuguchi H, Shimada K, Takahashi T, Kawase I, Kishimoto T, Naka T (2013) SOCS-1 gene delivery cooperates with cisplatin plus pemetrexed to exhibit preclinical antitumor activity against malignant pleural mesothelioma. Int J Cancer 132(2):459–471. doi:10.1002/ijc.27611 PubMedCrossRef

Titel: Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma
verfasst von: Lisa Arzt
Hannelore Kothmaier
Iris Halbwedl
Franz Quehenberger
Helmut H. Popper
Publikationsdatum: 01.07.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Virchows Archiv / Ausgabe 1/2014
Print ISSN: 0945-6317
Elektronische ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-014-1584-8

Springer Medizin

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

Abstract

Neu im Fachgebiet Pathologie

Assistierter Suizid durch Infusion von Thiopental

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Springer Medizin

Abstract

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