Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma

Our plain-English summary of Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma, by T.G. Johnson, K. Schelch, Y.Y. Cheng, et al (Journal of Thoracic Oncology, 2018).

The study

• Authors: T.G. Johnson, K. Schelch, Y.Y. Cheng, M. Williams, K.H. Sarun, M.B. Kirschner, S. Kao, A. Linton, S. Klebe, B.C. McCaughan, R.C.Y. Lin, C. Pirker, W. Berger, A. Lasham, N. van Zandwijk, G. Reid
• Journal: Journal of Thoracic Oncology
• Published: 2018;13(2):258-272
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterized by frequent chromosomal deletions of tumor suppressors, including microRNAs. MiR-137 plays a tumor suppressor role in other cancers, so the aim of this study was to characterize it and its target Y-box binding protein 1 (YBX1) in MPM.

Methods: Expression, methylation, and copy number status of miR-137 and its host gene MIR137HG were assessed by polymerase chain reaction. Luciferase reporter assays confirmed a direct interaction between miR-137 and Y-box binding protein 1 gene (YBX1). Cells were transfected with a miR-137 inhibitor, miR-137 mimic, and/or YBX1 small interfering RNA, and growth, colony formation, migration and invasion assays were conducted.

Results: MiR-137 expression varied among MPM cell lines and tissue specimens, which was associated with copy number variation and promoter hypermethylation. High miR-137 expression was linked to poor patient survival. The miR-137 inhibitor did not affect target levels or growth, but interestingly, it increased miR-137 levels by means of mimic transfection suppressed growth, migration, and invasion, which was linked to direct YBX1 downregulation. YBX1 was overexpressed in MPM cell lines and inversely correlated with miR-137. RNA interference-mediated YBX1 knockdown significantly reduced cell growth, migration, and invasion.

Conclusions: MiR-137 can exhibit a tumor-suppressive function in MPM by targeting YBX1. YBX1 knockdown significantly reduces tumor growth, migration, and invasion of MPM cells. Therefore, YBX1 represents a potential target for novel MPM treatment strategies.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This laboratory study examined miR-137, a microRNA (a small RNA that controls other genes), and its target gene YBX1 in malignant pleural mesothelioma. It did not measure asbestos exposure. The authors studied 11 mesothelioma cell lines and a non-cancer cell line (plus a larger, partly overlapping panel of 22 cell lines for some tests), tumors from 115 surgical patients in Sydney, 23 non-cancer samples, and 12 frozen tumors. miR-137 levels varied widely. In cell lines, this was linked to gene copy-number changes and to chemical silencing (methylation) of the gene. In both patient groups, high miR-137 was linked to shorter survival. Raising miR-137 slowed growth in seven of eight cell lines and reduced invasion in all cells tested. Blocking miR-137 had no significant effect on growth. miR-137 bound directly to YBX1 messenger RNA and lowered YBX1, which was consistently higher in mesothelioma cell lines than in the non-cancer line. Lowering YBX1 reduced growth in some cell lines. The authors concluded that YBX1 is a potential treatment target. They noted that the 12-sample group was small.

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 study using mesothelioma cell lines, stored patient tumor tissue with survival analysis, and mouse xenografts
• Who was studied: The study used 11 malignant pleural mesothelioma cell lines plus the non-cancer mesothelial cell line MeT-5A. A larger, partly overlapping panel of 22 cell lines was used for gene expression arrays and copy-number analyses. The study also used paraffin-embedded tumor samples from 115 patients who had extrapleural pneumonectomy (1994 to 2009) or pleurectomy and/or decortication (1991 to 2009) at Sydney hospitals. The controls were 23 non-cancer pleural and pericardium samples. A further 12 fresh frozen tumor samples came from surgery in 2009 to 2012.
• Exposure: No asbestos exposure was measured. The study measured miR-137 levels and tested the effects on cells of a miR-137 inhibitor, a miR-137 mimic, and small interfering RNA specific to YBX1.
• Main results:
  • Changes in the copy number of the miR-137 host gene were seen in seven of the 11 cell lines, with no significant correlation with expression in that panel. In the larger panel of 22 cell lines, miR-137 expression correlated significantly with host-gene copy number (Spearman's r = 0.58442, p = 0.00429).
  • The demethylating agent 5-aza-cytidine raised miR-137 in all cell lines, most markedly in the low-expressing ones. The four low-expressing cell lines showed high promoter methylation.
  • Patients with high miR-137 survived for a shorter time than those with low miR-137. This held both in the 115-patient paraffin-embedded cohort (p = 0.0065) and in the 12-sample fresh frozen cohort (p = 0.0218). High and low groups were defined by a more than twofold change from the cohort median.
  • In the 12 fresh frozen patient samples, copy number changes did not correlate with miR-137 expression. Of the six samples with relatively low expression, three showed higher methylation.
  • The miR-137 inhibitor had no significant effect on growth in any of the eight cell lines tested.
  • The miR-137 mimic significantly inhibited growth over 96 hours in seven of eight cell lines and disrupted colony formation in five of eight.
  • The miR-137 mimic significantly reduced the movement of the H28, VMC23 and SPC212 cell lines but not VMC40. It significantly reduced invasion in all mesothelioma cells tested.
  • A luciferase reporter test using the 3' untranslated region of YBX1 messenger RNA showed that miR-137 binds directly to it. The miR-137 mimic down-regulated YBX1 transcripts and lowered YBX1 protein in three of four cell lines.
  • YBX1 protein was inversely correlated with miR-137 (Spearman's r = -0.64693, p = 0.03145). YBX1 levels were consistently higher in the mesothelioma cell lines than in MeT-5A.
  • Knocking down YBX1 significantly decreased growth in the VMC23 and SPC212 cell lines and only moderately affected VMC40. H28 was unaffected by YBX1 knockdown alone, but its growth was significantly reduced when knockdown was combined with the miR-137 mimic.
• The authors' conclusion: The authors concluded that miR-137 is dysregulated in mesothelioma because of copy number variation and methylation of its host-gene promoter. They concluded that raising miR-137 inhibits the malignant characteristics of mesothelioma cells, at least partly by targeting YBX1, and that this points to potential targets for treatment.
• Limitations the authors state:
  • The fresh frozen patient series used to examine copy number in tumors was small (12 samples). The authors could not rule out a role for copy number variation and called for a larger series.

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, Asbestos Exposure.

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