CREB-induced inflammation is important for malignant mesothelioma growth.

Autor:	Westbom CM; Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont., Shukla A; Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont., MacPherson MB; Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont., Yasewicz EC; Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont., Miller JM; Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont., Beuschel SL; Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont., Steele C; Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama., Pass HI; Langone Medical Center, NYU School of Medicine, New York, New York., Vacek PM; Department of Medical Biostatistics, College of Medicine, University of Vermont, Burlington, Vermont., Shukla A; Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont. Electronic address: arti.shukla@uvm.edu.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2014 Oct; Vol. 184 (10), pp. 2816-27. Date of Electronic Publication: 2014 Aug 08.
DOI:	10.1016/j.ajpath.2014.06.008
Abstrakt:	Malignant mesothelioma (MM) is an aggressive tumor with no treatment regimen. Previously we have demonstrated that cyclic AMP response element binding protein (CREB) is constitutively activated in MM tumor cells and tissues and plays an important role in MM pathogenesis. To understand the role of CREB in MM tumor growth, we generated CREB-inhibited MM cell lines and performed in vitro and in vivo experiments. In vitro experiments demonstrated that CREB inhibition results in significant attenuation of proliferation and drug resistance of MM cells. CREB-silenced MM cells were then injected into severe combined immunodeficiency mice, and tumor growth in s.c. and i.p. models of MM was followed. We observed significant inhibition in MM tumor growth in both s.c. and i.p. models and the presence of a chemotherapeutic drug, doxorubicin, further inhibited MM tumor growth in the i.p. model. Peritoneal lavage fluids from CREB-inhibited tumor-bearing mice showed a significantly reduced total cell number, differential cell counts, and pro-inflammatory cytokines and chemokines (IL-6, IL-8, regulated on activation normal T cell expressed and secreted, monocyte chemotactic protein-1, and vascular endothelial growth factor). In vitro studies showed that asbestos-induced inflammasome/inflammation activation in mesothelial cells was CREB dependent, further supporting the role of CREB in inflammation-induced MM pathogenesis. In conclusion, our data demonstrate the involvement of CREB in the regulation of MM pathogenesis by regulation of inflammation. (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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