alexa Mesothelioma and Hypoxia: Modulation of the Inflammatio
ISSN: 1948-5956

Journal of Cancer Science & Therapy
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Research Article

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
Tel: +390652662604
Fax: +390652662505
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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Abstract

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.

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