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.

RETRACTED: MicroRNA‐379 suppresses osteosarcoma progression by targeting PDK1

“…vPrevious studies showed that aberrant expression of miR‐379 contributes to cancer development 31, 32, 33. For instance, Khan et al .…”

Human adipose mesenchymal stem cell-derived exosomal-miRNAs are critical factors for inducing anti-proliferation signalling to A2780 and SKOV-3 ovarian cancer cells

“…Member(s) of the hsa-miR-18114 and hsa-miR-29 families15 exhibit both anticancer and pro-cancer regulation under different clinical conditions, while members of hsa-miR-12616, hsa-miR-12917, hsa-miR-13618, hsa-miR-20419, hsa-miR-66320, hsa-miR-9921, hsa-miR-37822, hsa-miR-9223, and hsa-miR-40924 families are recognized as having anticancer properties under different clinical conditions. Families that contained at least one miRNA found in hAMSC-CM-derived exosomes reportedly exhibit antagonistic roles in numerous cancer types and include hsa-miR-48625, hsa-miR-10026, hsa-miR-10127, hsa-miR-12428, hsa-miR-128529, hsa-miR-13430, hsa-miR-13831, hsa-miR-13932, hsa-miR-14333, hsa-miR-18634, hsa-miR-19335, hsa-miR-20536, hsa-miR-22237, hsa-miR-33838, hsa-miR-33939, hsa-miR-42440, hsa-miR-12741, hsa-miR-2642, hsa-miR-10343, hsa-miR-10744, hsa-miR-12845, hsa-miR-14046, hsa-miR-14447, hsa-miR-15348, hsa-miR-19249, hsa-miR-21250, hsa-miR-21851, hsa-miR-2352, hsa-miR-2553, hsa-miR-37054, hsa-miR-37555, hsa-miR-38156, hsa-miR-41057, hsa-miR-4158, and hsa-miR-9359. These NGS data revealed an enriched miRNA population in hAMSC-CM-derived exosomes that are likely involved in the regulation of different types of cancer.…”

“…Exceptionally, hAMSC-CM derived exosomal miRNAs demonstrated outstanding diversity, which encompasses numerous anti-cancer miRNAs891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859, as well as new and poorly investigated miRNAs. In contrast, miRNAs, which are frequently detected in different cancers exosomes (include hsa-miR-105, hsa-miR-214, hsa-miR-92, hsa-miR-21, hsa-miR-29, hsa-miR-9, hsa-miR-222)6364, were either absent or showed very nominal expression in hAMSC-CM derived exosomes.…”

miR-379 Inhibits Cell Proliferation, Invasion, and Migration of Vascular Smooth Muscle Cells by Targeting Insulin-Like Factor-1

“…One study found that miR-379 levels are lower in circulating blood from patients with atherosclerotic coronary artery disease 18. In cancer studies, miR-379 was found to inhibit breast cancer cell proliferation by regulating cyclin B1 expression;21 Yamamoto reported that miR-379 inhibited cell growth of malignant pleural mesothelioma by targeting interleukin 18 23. In addition, miR-379 also exhibited a tumor-suppressive function in liver cancer 22.…”

“…miR-379 has also been found to inhibit cell growth in certain types of cancers including breast cancer, malignant mesothelioma, and liver cancer 212223. In this study, we investigated the functional role of miR-379 in the growth of VSMCs.…”