miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma

Our plain-English summary of miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma, by M. Williams, M.B. Kirschner, Y.Y. Cheng, et al (Oncotarget, 2015).

The study

• Authors: M. Williams, M.B. Kirschner, Y.Y. Cheng, J. Hanh, J. Weiss, N. Mugridge, C.M. Wright, A. Linton, S.C. Kao, J.J. Edelman, M.P. Vallely, B.C. McCaughan, W. Cooper, S. Klebe, R.C. Lin, H. Brahmbhatt, J. MacDiarmid, N. van Zandwijk, G. Reid
• Journal: Oncotarget
• Published: 2015;6(27):23480-95
• Cited by: 67 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR-193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi-mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated with increased apoptosis. In conclusion, miR-193a-3p appears to have importance in the biology of MPM and may represent a target for therapeutic intervention.

In plain English

This laboratory study, by researchers in Sydney, Australia, looked at microRNAs, small molecules that help control genes, in malignant pleural mesothelioma. The authors describe this cancer as asbestos-induced, but the study did not measure anyone's asbestos exposure. The authors compared stored tumor samples from 59 patients who had extrapleural pneumonectomy and 61 who had pleurectomy with or without decortication (operated on between 1991 and 2009) with 23 samples of normal pleura. Two microRNAs, miR-193a-3p and miR-192, were significantly lower in tumors. In the extrapleural pneumonectomy group they were 3.1-fold and 2.8-fold lower. In the pleurectomy group they were 2.2-fold and 2.1-fold lower. Levels did not differ significantly by tumor subtype or stage. In mesothelioma cells grown in the lab, adding a synthetic copy of miR-193a-3p slowed growth and increased cell death, along with lower levels of a protein called MCL-1. It did not make the cells more sensitive to gemcitabine, pemetrexed or cisplatin. In nude mice carrying human mesothelioma tumors, miR-193a-3p delivered in bacterially derived minicells slowed tumor growth. The authors concluded that this approach may have potential as a treatment option.

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: comparison of stored tumor and normal pleura samples (retrospective), experiments in mesothelioma cell lines, and a mouse xenograft experiment
• Who was studied: Tumor samples from malignant pleural mesothelioma patients operated on at Royal Prince Alfred Hospital or Strathfield Private Hospital, Sydney, between 1991 and 2009: 59 extrapleural pneumonectomy (EPP) and 61 pleurectomy with or without decortication (P/D) patients, plus 23 normal pleura control samples. Also studied: mesothelioma cell lines, and nude mice implanted with MSTO-211H mesothelioma cells (6 given miR-193a-3p, 6 given miR-16, 5 given control mimic).
• Exposure: No asbestos exposure was measured. The study measured microRNA levels and tested synthetic microRNA mimics (miR-193a-3p, miR-192) in cells, and miR-193a-3p delivered to mice in EGFR-targeted bacterially derived minicells (EDVs).
• Main results:
  • In EPP tumor samples compared with normal pleura, miR-193a-3p was reduced 3.1-fold (P = 2.39 × 10 to the power of minus 6) and miR-192 was reduced 2.8-fold (P = 0.0007).
  • In P/D tumor samples, miR-193a-3p was reduced 2.2-fold (P = 0.00001) and miR-192 was reduced 2.1-fold (P = 0.0001). The other microRNAs showed no significant change.
  • In both patient groups, microRNA levels did not differ significantly between tumors of different histological subtype or stage.
  • In the lab, the miR-193a-3p mimic caused time- and dose-dependent growth inhibition in all mesothelioma cell lines tested. Neither mimic inhibited growth of the immortalized mesothelial line MeT-5A.
  • Neither miR-192 nor miR-193a-3p increased the cells' sensitivity to gemcitabine, pemetrexed or cisplatin.
  • Switching off MCL-1 directly produced growth effects similar to the miR-193a-3p mimic. In MSTO cells, over half the cells were late apoptotic or necrotic (dying or dead) after miR-193a-3p, and 25% after MCL-1 silencing.
  • In the mouse xenograft model, minicells containing miR-193a-3p inhibited tumor growth to a similar extent as miR-16, giving smaller tumors with more apoptosis (p = 0.015, Wilcoxon signed rank test).
• The authors' conclusion: The authors concluded that miR-192 and miR-193a-3p are downregulated in MPM tumors. They found that restoring miR-193a-3p inhibited growth in cell lines and in mouse tumors, and suggested that targeted delivery of a miR-193a-3p mimic may have potential as a therapeutic option for patients with MPM.
• Limitations the authors state:
  • The authors note that the EGFR expression of the MSTO cell line used probably contributed to the success of the minicell treatment. They also note that sarcomatoid tumors appear to lack EGFR, so other targets would be needed for those tumors.
  • miR-205 was detected at very low levels and only in some samples, and miR-203 levels were extremely variable in both tumor and pleura samples.

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, Prognosis, Adenocarcinoma, Pleura, Apoptosis, Necrosis.

Related studies

• ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma — Y.Y. Cheng, M.B. Kirschner, et al. (2013)
• Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma — G. Reid, M.E. Pel, et al. (2013)
• Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma — S.C. Kao, Y.Y. Cheng, et al. (2017)
• MiR-score: a novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma — M.B. Kirschner, Y.Y. Cheng, et al. (2015)
• Increased circulating miR-625-3p: a potential biomarker for patients with malignant pleural mesothelioma — M.B. Kirschner, Y.Y. Cheng, et al. (2012)
• Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma — T.G. Johnson, K. Schelch, et al. (2018)

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