MiR-379/411 cluster regulates IL-18 and contributes to drug resistance in malignant pleural mesothelioma

Our plain-English summary of MiR-379/411 cluster regulates IL-18 and contributes to drug resistance in malignant pleural mesothelioma, by K. Yamamoto, M. Seike, S. Takeuchi, et al (Oncology Reports, 2014).

The study

• Authors: K. Yamamoto, M. Seike, S. Takeuchi, C. Soeno, A. Miyanaga, R. Noro, Y. Minegishi, K. Kubota, A. Gemma
• Journal: Oncology Reports
• Published: 2014;32(6):2365-72
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This was a laboratory study of six malignant pleural mesothelioma (MPM) cell lines. It did not study patients or asbestos exposure. The authors tested how the cells responded to two drugs, pemetrexed (PEM) and vorinostat (SAHA). Only one line, 211H, was classed as sensitive to both, and three (H2452, MESO1, MESO4) were resistant to both. Activity of the IL-18 gene, which makes a signalling molecule, was significantly higher in the resistant and intermediate lines than in 211H. Two small regulatory RNAs, miR-379 and miR-411, were lower in resistant lines: miR-379 in all three and miR-411 in two. Lab tests indicated that both act directly on the IL-18 gene. In MESO1 cells, adding miR-411, or silencing IL-18, significantly reduced the cells' ability to invade through a filter. Adding both RNAs together showed a trend toward better PEM sensitivity and appeared to increase SAHA sensitivity. With SAHA, MESO1 cells given both RNAs needed 1.0 µM to halve growth, against 8.1 µM without them. The authors concluded that this miR-379/411 cluster may be a new treatment target for advanced MPM, depending on IL-18 levels.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) study of human mesothelioma cell lines, using drug growth-inhibition tests, gene and microRNA profiling, reporter assays and invasion assays
• Who was studied: six malignant pleural mesothelioma cell lines (NCI-H28, NCI-H2452 and ACC-MESO4 described as epithelial-type; NCI-H2052 sarcomatoid-type; ACC-MESO1 fibroblast-type; MSTO-211H biphasic-type), obtained from the American Type Culture Collection and the Riken Cell Bank in 2008 to 2009; work done at Nippon Medical School, Tokyo
• Exposure: No asbestos exposure was studied. Cell lines were treated with pemetrexed (PEM) and vorinostat (SAHA) at 0 to 100 µM, and with miR-379 and miR-411 mimics or siRNA silencing IL-18
• Main results:
  • 211H was the only cell line sensitive to both drugs. In Table I, the PEM IC50 was 0.07 µM for 211H and H28, 0.57 µM for H2052, and above 100 µM for H2452, MESO1 and MESO4. The SAHA IC50 was 3.3 µM for 211H and 7.2 to 9.2 µM for the other lines
  • In microarray analysis, IL-18 gene expression was significantly higher in the resistant and intermediate-sensitivity cell lines than in the sensitive 211H line (one of 16 genes differing, fold change >1.5, P<0.05)
  • In targeted cytokine testing, IL-18 was the most upregulated of 6 detectable cytokine genes in the three drug-resistant lines, while IL-8 was highest in the sensitive and intermediate lines
  • miR-379 was lower in all three drug-resistant lines, and miR-411 in two of them, compared with 211H
  • In H28 cells, miR-379 or miR-411 mimics significantly reduced activity of a reporter carrying part of the IL-18 gene. The authors interpreted this as IL-18 being a direct target of both
  • In MESO1 cells, miR-411 alone, or IL-18 silencing, significantly reduced invasion; the combination of both mimics reduced it further
  • In MESO1 cells, the combined mimics gave a trend toward improved PEM sensitivity
  • In MESO1 cells, the combined mimics appeared to increase SAHA sensitivity: SAHA IC50 1.0 µM in transfected cells versus 8.1 µM in parental cells. No statistical test is reported for this, and no comparable IC50 change is reported for PEM
• The authors' conclusion: The authors concluded that IL-18 may be a key determinant of sensitivity to PEM and SAHA in MPM cells, and that the miR-379/411 cluster may be a new therapeutic target for advanced MPM patients, depending on IL-18 expression

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pemetrexed (Alimta), Cytokine.

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