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MicroRNA Signature of Malignant Mesothelioma with Potential Diagnostic and Prognostic Implications

¹ Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, University of Piemonte Orientale, Novara, Italy; ² Molecular Cancer Genetics Group, Istituto FIRC di Oncologia Molecolare, Milan, Italy; ³ Scientific Directorate Fondazione Istituto di Ricerca e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy; ⁴ Laboratory of Cancer Genomics, Fondo Edo Tempia, Biella, Italy; ⁵ Department of Anatomic Pathology, Dell'Angelo Hospital, Zelarino, Italy; and ⁶ Department of Medicine, Local Health Unit 11, Borgosesia, Italy

Correspondence and requests for reprints should be addressed to Giovanni Gaudino, Ph.D., Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Via Bovio 6, 28,100 Novara, Italy. E-mail: ggaudino{at}crch.hawaii.edu

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 human mesothelial cells (HMC–telomerase reverse transcriptase). Microarray profiling, confirmed by real-time quantitative RT-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 terms of Gene Ontology (GO) that are associated with the development and progression of mesothelioma. This suggests 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 quantitative RT-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. Notably, the reduced expression of two miRNAs (miR-17–5p and miR-30c) correlated with better survival of patients with sarcomatoid subtype. Our preliminary analysis points at 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 • real-time quantitative RT-PCR • survival

CLINICAL RELEVANCE This work reveals that several microRNAs (miRNAs) are differentially expressed in malignant mesothelioma and in mesothelial cells. Some of their putative target genes are associated with the etiology of malignant mesothelioma. This study demonstrates dysregulated miRNAs as potential diagnostic biomarkers and as prognostic factors for malignant mesothelioma.