SMO expression level correlates with overall survival in patients with malignant pleural mesothelioma

Yi Zhang,Biao He,Dongsheng Yue,Fang Zhang,Hui Li,Jianxing He,Changli Wang,Natalie Lui,David M Jablons

doi:10.1186/1756-9966-32-7

Abstract

BackgroundMalignant mesothelioma is an aggressive, treatment-resistant tumor arising from mesothelium of pleura, peritoneum and pericardium. Despite current combined regimen, its prognosis remains dismal, calling for more effective targeted therapies. We investigated whether aberrant Hh activation may play a role in mesothelioma.MethodsSMO and SHH expression levels were analyzed in 46 mesothelioma tissue specimens with real-time RT-PCR, and correlation with survival was analyzed with univariate and multivariate Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test. We also examined multiple mesothelioma cell lines for SMO expression and the effect of Hh inhibition by a specific SMO antagonist on cell proliferation by MTS assay.ResultsWe observed strong correlation between higher SMO and SHH expression levels with poorer overall survival. Remarkably, Hh inhibition by a specific SMO inhibitor significantly suppressed cell proliferation in the mesothelioma cell lines examined.ConclusionOur data strongly support that Hh signaling deregulation plays critical roles in proliferation of mesothelioma, and consistently exerts significant impact on prognosis of the disease. Therefore our findings revealed the hitherto unappreciated role of Hh activation in mesothelioma, and pinpointed Hh signaling antagonist as a potential new therapy against this devastating disease.

Highlights

Malignant mesothelioma is an aggressive, treatment-resistant tumor arising from mesothelium of pleura, peritoneum and pericardium
We examined multiple mesothelioma cell lines for SMO expression and their cell proliferation responses to a specific SMO inhibitor
Patients Forty-six patients underwent surgical resection for malignant pleural mesothelioma at our institution, had tissue specimens deposited at our tissue bank and available for use

Summary

Introduction

Malignant mesothelioma is an aggressive, treatment-resistant tumor arising from mesothelium of pleura, peritoneum and pericardium. Malignant mesothelioma is an aggressive, treatmentresistant tumor, arising from transformed mesothelial cells lining the pleura, peritoneum and pericardium. Patients with malignant pleural mesothelioma (MPM) usually present with shortness of breath and chest pain with pleural effusions. The pathogenic mechanisms underlying mesothelioma involve deregulation of multiple signaling pathways, including activation of multiple receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) family and MET, and subsequent deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades, the TNF-α / NF-κB survival pathway, Wnt signaling, and loss of tumor suppressors such as Neurofibromatosis type 2(NF2), p16INK4A, and p14ARF [5,6,7]. Understanding mechanisms of the dysregulated signaling pathways allows strategies for development of targeted new therapies against this devastating disease

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