Mesothelioma and Hypoxia: Modulation of the Inflammation-Related Phenotype and Identification of Prognostic Markers
|Linda Ravenna1,2, Irene Cardillo2, Gianfranca Curzio2, Alfonso Baldi3, Manlio Mattioni2, Bruno Vincenzi4, Matteo Antonio Russo5,
Silvia Soddu6 and Alessandra Verdina2*
|1Department of Biomedical Sciences, CNR, Rome, 00185, Italy|
|2Department for the development of therapeutic programs, Regina Elena National Cancer Institute, Rome, 00144, Italy|
|3Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, 80138, Italy|
|4Department of Medical Oncology, Campus Biomedico University, Rome, 00161, Italy|
|5IRCSS San Raffaele Pisana Rome, 00163, Italy|
|6Department of Experimental Oncology, Regina Elena National Cancer Institute, Rome, 00144, Italy|
|Corresponding Author :||Alessandra Verdina
Istituti Fisioterapici Ospitalieri - Via Elio Chianesi
53 00144 Roma, Italy
E-mail: [email protected]
|Received July 17, 2014; Accepted September 24, 2014; Published September 29, 2014|
|Citation: Ravenna L, Cardillo I, Curzio G, Baldi A, Mattioni M, et al. (2014) Mesothelioma and Hypoxia: Modulation of the Inflammation-Related Phenotype and Identification of Prognostic Markers. J Cancer Sci Ther 6:378-387. doi:10.4172/1948-5956.1000296|
|Copyright: © 2014 Ravenna L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
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Objective: Malignant Mesothelioma is an aggressive tumor occurring in the context of chronic inflammation and characterized by hypoxic areas. This study explores how hypoxia impacts on the pro-inflammatory phenotype of MSTO-211H and MPP89 mesothelioma cells and investigates the role of HIF-1 alpha and NF-kB in this process. The prognostic values of two molecules upregulated by oxygen deprivation, HIF-3 alpha and CXCR4, is also analyzed.
Methods: Hypoxic condition was obtained in a sealed modular incubator chamber flushed with 1% O2. mRNA and protein levels were evaluated by real-time PCR and western blot. Silencing of HIF-1alpha was achieved by specific shRNA and NF-kB inhibition by parthenolide treatment. HIF-3 alpha and CXCR4 expression in tumor tissues from mesothelioma patients was detected by immunohistochemistry.
Results: The hypoxic stimulation of mesothelioma cells induced an early activation of HIF-1 alpha and NF-kB and a later increase of HIF-3 alpha expression. In addition, the upregulation of a set of inflammation-related genes was observed. Silencing of HIF-1 alpha and treatment with parthenolide highlighted that the observed increase in gene expression depends on both HIF-1 alpha and NF-kB transcriptional activity. A correlation between high expression of CXCR4 in human mesothelioma samples and poor survival was also observed and HIF3 alpha was suggested as a potential new prognostic marker.
Conclusions: This study evidences a cross-talk between hypoxia adaptation and pro-inflammatory phenotype in mesothelioma accomplished through the combined transactivation activity of HIFs and NFkB. Immunohistochemistry analysis of tissue samples confirms CXCR4 and suggests HIF-3 alpha as potential prognostic markers for mesothelioma.