Research Article Four-miRNA Signature to Identify Asbestos- Related Lung Malignancies Lory Santarelli 1 , Simona Gaetani 1 , Federica Monaco 1 , Massimo Bracci 1 , Matteo Valentino 1 , Monica Amati 1 , Corrado Rubini 2 , Armando Sabbatini 3 , Ernesto Pasquini 4 , Nunzia Zanotta 5 , Manola Comar 5,6 , Jiri Neuzil 7,8 , Marco Tomasetti 1,9 , and Massimo Bovenzi 6 Abstract Background: Altered miRNA expression is an early event upon exposure to occupational/environmental carcinogens; thus, identification of a novel asbestos-related profile of miRNAs able to distinguish asbestos-induced cancer from cancer with different etiology can be useful for diagnosis. We therefore performed a study to identify miRNAs associated with asbestos-induced malignancies. Methods: Four groups of patients were included in the study, including patients with asbestos-related (NSCLC Asb ) and asbestos-unrelated non–small cell lung cancer (NSCLC) or with malignant pleural mesothelioma (MPM), and disease- free subjects (CTRL). The selected miRNAs were evaluated in asbestos-exposed population. Results: Four serum miRNAs, that is miR-126, miR-205, miR-222, and miR-520g, were found to be implicated in asbestos-related malignant diseases. Notably, increased expression of miR-126 and miR-222 were found in asbestos- exposed subjects, and both miRNAs are involved in major pathways linked to cancer development. Epigenetic changes and cancer-stroma cross-talk could induce repression of miR-126 to facilitate tumor formation, angiogenesis, and invasion. Conclusions: This study indicates that miRNAs are poten- tially involved in asbestos-related malignancies, and their expression outlines mechanism(s) whereby miRNAs may be involved in an asbestos-induced pathogenesis. Impact: The discovery of a miRNA panel for asbestos- related malignancies would impact on occupational com- pensation and may be utilized for screening asbestos-exposed populations. Introduction Although asbestos use has been banned or restricted, exposure to asbestos is still widespread around the world. Besides the occupational exposure, a great number of people are affected by environmental or domestic exposure to asbestos (1). This results in serious risk of developing malignant pleural mesothelioma (MPM) and lung cancer (LC; refs. 2–4). The association between asbestos exposure and lung adenocarcinoma is well established (5). Nevertheless, precise histopathologic data are poorly under- stood when investigating the asbestos-cancer link. Although the Helsinki criteria for identifying individuals with high occupational risk of asbestos exposure have been accepted, it is insufficient, and specific asbestos-related parameters are need- ed. The presence of pleural plaques is not considered a precan- cerous condition, while asbestos and smoking are associated with increased risk of lung cancer. Various candidates for biomarkers of asbestos-related malignancies have been proposed (6–8). How- ever, most of the tumor markers are derived from molecules produced and secreted from cancer cells. This means that when the tumor mass is relatively small, the levels of certain tumor markers in serum are initially low and gradually increasing as the tumor develops. Recently, miRNAs have become attractive entities for profil- ing cancer. miRNA expression is altered soon after exposure to occupational and environmental carcinogens (9). It therefore appears of importance to identify a novel asbestos-related profile able to distinguish asbestos-induced cancer from cancer with different etiology. Here, a sequential phase study has been performed to identify a panel of serum miRNAs associated with development of asbestos-induced thoracic malignancies (LC and MPM). The identified miRNA panel has potential clinical value for early detection of asbestos-induced malignan- cies and may be utilized for screening high-risk populations exposed to asbestos. Materials and Methods Ethics statement All subjects filled a questionnaire including their informed written consent. The study was carried out according to the 1 Department of Clinical and Molecular Sciences, Section of Occupational Medicine, Polytechnic University of Marche, Ancona, Italy. 2 Department of Biomedical Sciences and Public Health, Section of Anatomical Pathology, Polytechnic University of Marche, Ancona, Italy. 3 Division of Thoracic Surgery, United Hospitals, Ancona, Italy. 4 ENT Metropolitan Unit, Bellaria Hospital, AUSL Bologna, Bologna, Italy. 5 Institute for Maternal and Child Health-IRCCS "Burlo Garofolo," Trieste, Italy. 6 Department of Medical Sciences, University of Trieste, Trieste, Italy. 7 Mitochondria, Apoptosis and Cancer Research Group, School of Medical Science, Griffith University, Southport, Australia. 8 Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. 9 International Society of Doctors for the Environment (ISDE), Arezzo, Italy. Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/). Corresponding Authors: Marco Tomasetti, Polytechnic University of Marche, Via Tronto 10, Ancona 60126, Italy. Phone: 39-071-2206063; Fax: 39-071-2206062; E-mail: m.tomasetti@staff.univpm.it; Lory Santarelli, l.santarelli@staff.univpm.it doi: 10.1158/1055-9965.EPI-18-0453 Ó2018 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention www.aacrjournals.org 119 on July 5, 2020. © 2019 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from Published OnlineFirst September 26, 2018; DOI: 10.1158/1055-9965.EPI-18-0453