Mesothelioma and Hypoxia: Modulation of the Inflammation-Related Phenotype and Identification of Prognostic Markers
- *Corresponding Author:
- Alessandra Verdina
Istituti Fisioterapici Ospitalieri - Via Elio Chianesi
53 00144 Roma, Italy
E-mail: [email protected]
Received date: July 17, 2014; Accepted date: September 24, 2014; Published date: 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.
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.