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Published ahead of print on June 5, 2009
Am. J. Respir. Cell Mol. Biol. 2009, doi:10.1165/rcmb.2009-0060OC
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Submitted on February 15, 2009
Accepted on June 3, 2009

MicroRNA Signature of Malignant Mesothelioma with Potential Diagnostic and Prognostic Implications

Sara Busacca1, Serena Germano1, Loris De Cecco2, Maurizio Rinaldi1, Federico Comoglio1, Francesco Favero3, Bruno Murer4, Luciano Mutti5, Marco Pierotti6, and Giovanni Gaudino7*

1 DISCAFF, University of Piemonte Orientale "A. Avogadro", Novara, Italy, 2 Molecular Cancer Genetics Group, IFOM, Milan, MI, Italy; Scientific Directorate Fondazione IRCCS Istituto Nazionale Tumori, Milan, MI, Italy, 3 Laboratory of Cancer Genomics, Fondo Edo Tempia, Biella, BI, Italy, 4 Anatomic Pathology, Dell'Angelo Hospital, Zelarino, VE, Italy, 5 Medicine, Local Health Unit 11, Borgosesia, vc, Italy, 6 Molecular Cancer Genetics Group, IFOM, Milan, MI, Italy; Scientific Directorate, IRCCS Istituto Nazionale Tumori, Milan, MI, Italy, 7 DISCAFF, University of Piemonte Orientale "A. Avogadro", via Bovio 6, Novara, NO, Italy

* To whom correspondence should be addressed. E-mail: giovanni.gaudino{at}unipmn.it.

MicroRNAs (miRNAs) post-transcriptionally regulate the expression of target genes and may behave as oncogenes or tumor suppressors. Human malignant mesothelioma is an asbestos-related cancer, with poor prognosis and low median survival. Here we report for the first time a cross-evaluation of miRNA expression in mesothelioma (MPP-89, REN) and mesothelial cells (HMC-TERT). Microarray profiling, confirmed by Real Time quantitative RT-PCR (qRT-PCR), revealed a differential expression of miRNAs between mesothelioma and mesothelial cells. In addition, a computational analysis combining miRNA and gene expression profiles allowed the accurate prediction of genes potentially targeted by dysregulated miRNAs. Several predicted genes belong to Gene Ontology (GO) terms associated to the development and progression of mesothelioma, suggesting that miRNAs may be key players in mesothelioma oncogenesis. We further investigated miRNA expression on a panel of 24 mesothelioma specimens, representative of the three histotypes (epithelioid, biphasic and sarcomatoid), by qRT-PCR. The expression of miR-17-5p, miR-21, miR-29a, miR-30c, miR-30e-5p, miR-106a and miR-143 was significantly associated with the histopathological subtypes. Noteworthy, the reduced expression of two miRNAs (miR-17-5p and miR-30c) correlated with better survival of patients with sarcomatoid subtype. Our preliminary analysis suggests miRNAs as potential diagnostic and prognostic markers of mesothelioma and suggests novel tools for the therapy of this malignancy.
Key words: human malignant mesothelioma • microRNAs • microarray • target prediction • survival






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