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.
Highlights
Pleural Malignant Mesothelioma (MM) is one of the most aggressive solid tumors
This study evidences a cross-talk between hypoxia adaptation and pro-inflammatory phenotype in mesothelioma accomplished through the combined transactivation activity of Hypoxia inducible factor (HIF) and NFkB
We explored the role of HIF-1 alpha and nuclear factor-kappa B (NF-kB) in the inflammationrelated gene expressions in hypoxic MM cells in order to clarify their role on MM progression and to identify potential prognostic markers
Summary
It has a poor prognosis due to its resistance to chemo and radiotherapy and to the difficulty in administering anticancer drugs into the pleural tissue [1,2]. Even though it is a rare tumor, its incidence is on the rise and approximately 250,000 deaths are estimated to occur in Western Europe over the 30 years. Asbestos exposure generates reactive oxygen and nitrogen species and stimulates macrophages and other cell types to produce different cytokines and growth factors. In MM, little is known about the inflammation-related molecules produced by tumor cells. Vascular epidermal growth factor A (VEGF) showed to play a significant role in MM, where a correlation with survival was observed [12]
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