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• W2000405555 abstract "Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DCMalignant pleural mesothelioma (MPM) is an aggressive tumor caused by former asbestos exposure with a mean overall survival of 12 months from diagnosis. The knowledge about predictive factors of outcome is poor and MPM is resistant to conventional therapy. The long latency period in MPM pathogenesis as well as the absence of early symptoms is responsible for the late diagnosis of this disease.From our recent study and published data we know that the regular rapid progressive type of MPM uses several signaling pathways regulating cell growth and survival. Asbestos causes genetic modifications, most notably the upregulation of cell survival and growth signaling pathways as well as the expression of other proteins that favor the resistance of MPM to apoptosis and chemotherapy. In order to develop more effective therapy than the currently used chemotherapy, novel targets have to be identified in MPM.The JAK/STAT signaling pathway is the principal signaling mechanism for lots of cytokines or growth factors in mammalians. JAK activation induces a variety of biological responses like cell proliferation, differentiation, cell migration, and apoptosis.Our investigations demonstrate that the STAT signaling pathway is totally deregulated: STAT1 is upregulated, whereas STAT3 is downregulated. SOCS1 and SOCS3 - which represent a negative feedback loop and which are regulators of STAT1 and STAT3 - are totally missing in MPM. Investigations in six mesothelioma cell lines showed that STAT1 is highly expressed and that SOCS1 is missing whereas the expression of pSTAT1 (Tyr701) can be stimulated and therefore be increased by Interferon-gamma treatment. The expression levels of other components of the STAT signaling pathway in these cell lines are currently under investigation.It is known that protein expression is controlled by noncoding RNAs, e.g. microRNAs (miRNA) and we investigated the possible impact of miRNAs on the STAT signaling pathway in MPM. We identified miR-30d* as a regulator of phosphorylated STAT1 (Ser727). Furthermore we found that miR-19b, miR-30b, miR-30c and miR-222 are upregulated which are predicted to target SOCS1 and SOCS3 - this could be an explanation for the missing expression of these proteins. MiR-21 is extremely upregulated in MPM, a miRNA that is associated with a wide variety of human tumors and which targets STAT3.Understanding the role of STATs in MPM could be the first step into the development of a targeted therapy for these tumors.Citation Format: Lisa Arzt, Franz Quehenberger, Iris Halbwedl, Helmut H. Popper. STAT signaling is totally deregulated in malignant pleural mesothelioma: What are the reasons. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5267. doi:10.1158/1538-7445.AM2013-5267" @default.
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• W2000405555 date "2013-04-15" @default.
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• W2000405555 title "Abstract 5267: STAT signaling is totally deregulated in malignant pleural mesothelioma: What are the reasons." @default.
• W2000405555 doi "https://doi.org/10.1158/1538-7445.am2013-5267" @default.
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