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

Journal of Experimental & Clinical Cancer Research

Natalie Lui³  Biao He³  David M Jablons³  Changli Wang⁵  Dongsheng Yue⁵  Hui Li³  Fang Zhang¹  Jianxing He⁴  Yi Zhang² 

[1] Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, 314006, Jiaxing, Zhejiang, China;Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China;Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehen-sive Cancer Center, University of California, 94143, San Francisco, CA, USA;Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangzhou Medical College, State Key Laboratory of Respiratory Disease, Guangzhou, China;Department of Lung Cancer, Tianjin Medical University Cancer Institute & Hospital, 300060, Tianjin, China

关键词: Proliferation suppression;    Prognosis;    Hedgehog signaling;    Mesothelioma;   

Others  :  825442
DOI  :  10.1186/1756-9966-32-7

 received in 2012-10-24, accepted in 2013-02-01,  发布年份 2013

【 摘 要 】

Background

Malignant 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.

Methods

SMO 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.

Results

We 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.

Conclusion

Our 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.

【 授权许可】

   
2013 Zhang et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Bianchi C, Bianchi T: Malignant mesothelioma: global incidence and relationship with asbestos. Ind Health 2007, 45(3):379-387.
• [2]Robinson BW, Musk AW, Lake RA: Malignant mesothelioma. Lancet 2005, 366(9483):397-408. Review
• [3]Mott FE: Mesothelioma: a review. Ochsner J. 2012, 12(1):70-79.
• [4]Rusch VW: A proposed new international TNM staging system for malignant pleural mesothelioma. Chest 1995, 108(4):1122-1128.
• [5]Heintz NH, Janssen-Heininger YM, Mossman BT: Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways. Am J Respir Cell Mol Biol 2010, 42(2):133-139. Review
• [6]Sekido Y: Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells. Cancer Sci 2010, 101(1):1-6.
• [7]Uematsu K, Seki N, Seto T, Isoe C, Tsukamoto H, Mikami I, You L, He B, Xu Z, Jablons DM, Eguchi K: Targeting the Wnt signaling pathway with dishevelled and cisplatin synergistically suppresses mesothelioma cell growth. Anticancer Res 2007, 27(6B):4239-4242.
• [8]Shi Y, Moura U, Opitz I, Soltermann A, Rehrauer H, Thies S, Weder W, Stahel RA, Felley-Bosco E: Role of hedgehog signaling in malignant pleural mesothelioma. Clin Cancer Res 2012, 18(17):4646-4656.
• [9]Varjosalo M, Taipale J: Hedgehog: functions and mechanisms. Genes Dev 2008, 22:2454-2472.
• [10]Yang L, Xie G, Fan Q, Xie J: Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene 2010, 29:469-481.
• [11]Scales SJ, de Sauvage FJ: Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci 2009, 30:303-312.
• [12]Ma X, Chen K, Huang S: Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis 2005, 26:1698-1705.
• [13]Hooper JE, Scott MP: Communicating with Hedgehogs. Nat Rev Mol Cell Biol 2005, 6:306-317.
• [14]Huangfu D, Anderson KV: Signaling from Smo to Ci/ Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 2006, 133:3-14.
• [15]Osterlund T, Kogerman P: Hedgehog signalling: how to go from Smo to Ci and Gli. Trends Cell Biol 2006, 16:176-180.
• [16]Ruiz i Altaba A, Sanchez P, Dahmane N: Gli and hedgehog in cancer: tumors, embryos and stem cells. Nat Rev Cancer 2002, 2:361-372.
• [17]Bi X, Han X, Zhang F, He M, Zhang Y, Zhi XY, Zhao H: Triparanol suppresses human tumor growth in vitro and in vivo. Biochem Biophys Res Commun 2012, 425(3):613-618.
• [18]Zhang F, Phiel CJ, Spece L, Gurvich N, Klein PS: Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. J Biol Chem 2003, 278(35):33067-33077.