title: MiR-379/411 cluster regulates IL-18 and contributes to drug resistance in malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence in Japan. In this study, we performed gene and microRNA (miRNA) expression profiling to identify novel therapeutic targets in MPM cells. Based on relative sensitivities to pemetrexed (PEM) and the histone deacetylase (HDAC) inhibitor, vorinostat (SAHA), 211H cells were determined to be the only sensitive MPM cell line out of the 6 tested. On the same series of cell lines, we performed whole genome transcriptomic profiling via DNA microarrays and pathway analysis of the derived data. Of particular note, IL-18 gene expression levels were significantly higher in the cell lines that were either drug resistant or displayed intermediate sensitivity, compared to the sensitive 211H cell line. Pathway analysis revealed IL-18 as an important gene associated with drug sensitivity of MPM cells. A relationship between IL-18 overexpression and drug resistance was also observed following targeted assessment of 10 cytokine genes using quantitative RT-PCR. miRNA expression profiles were evaluated in the MPM cell line panel in order to discern the mechanism of IL-18 induction in the drug-resistant lines. We found that miR-379 and miR-411 belonged to the same cluster of miRNAs located on chromosome 14q32 that commonly target the IL-18 gene. Luciferase reporter assays revealed that miR-379 and miR-411 directly target the IL-18 gene. Introduction of miR-379 plus miR-411, as well as IL-18 silencing, significantly suppressed the invasive capacity of MESO1 cells in vitro. Furthermore, the use of either PEM or SAHA together with miR-379 plus miR-411 mimics mediated increased sensitivity to these drugs in MESO1 cells. These results suggest that the miR-379/411 cluster may provide new therapeutic opportunities for advanced MPM patients, depending on the nature of IL-18 gene expression.
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Seike
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Soeno
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Miyanaga
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Noro
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Minegishi
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Gemma
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D020382:Interleukin-18 / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000086002:Mesothelioma, Malignant; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D005971:Glutamates; D006877:Hydroxamic Acids; D020382:Interleukin-18; C561022:MIRN379 microRNA, human; C582326:MIRN411 microRNA, human; D035683:MicroRNAs; D000068437:Pemetrexed; D000077337:Vorinostat; D006147:Guanine