miR-182 and miR-183 Promote Cell Proliferation and Invasion by Targeting FOXO1 in Mesothelioma

Our plain-English summary of miR-182 and miR-183 Promote Cell Proliferation and Invasion by Targeting FOXO1 in Mesothelioma, by R. Suzuki, V.J. Amatya, K. Kushitani, et al (Frontiers in Oncology, 2018).

The study

• Authors: R. Suzuki, V.J. Amatya, K. Kushitani, Y. Kai, T. Kambara, Y. Takeshima
• Journal: Frontiers in Oncology
• Published: 2018;8:446
• Cited by: 44 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Dysregulation of miR-182 and miR-183 has been implicated in the progression of several human cancers. Our previous study showed that miR-182 and miR-183 are upregulated in malignant mesothelioma. However, their biological functions remain unclear. We performed in-situ hybridization to analyze the expression of miR-182 and miR-183 in human tissues. Functional analysis was performed by treatment of two mesothelioma cell lines (ACC-MESO1 and CRL-5915) with miR-182 and miR-183 inhibitors. RT-PCR and western blot analysis were conducted to analyze the expression of FOXO1, a known target of both miR-182 and miR-183. Mesothelioma cells treated with FOXO1 siRNA and miR-182/183 inhibitors were also analyzed by evaluating cell proliferation and invasion, as well as expression of FOXO1 and its downstream targets. We confirmed miR-182 expression in 25/29 cases and miR-183 expression in 29/29 cases of human mesothelioma tissue by in-situ hybridization. Notably, inhibition of miR-182 or miR-183 reduced cell proliferation, invasion, migration, and adhesion abilities of mesothelioma cells. Surprisingly, transfection with both miR-182 and miR-183 inhibitors showed even more effects on cell progression. Furthermore, FOXO1 was identified as a target of miR-182 and miR-183 in mesothelioma cells. Inhibition of miR-182 and miR-183 reduced cell proliferation ability via upregulation of FOXO1 and its downstream targets, namely, p27. Moreover, inhibition of miR-182 and miR-183 reduced the cell invasion properties of mesothelioma cells. Our findings indicated that miR-182 and miR-183 promote mesothelioma cell progression via downregulation of FOXO1 and p27. Targeting the miR-182/183-FOXO1 axis could serve as a novel treatment against malignant mesothelioma.

In plain English

This was a laboratory study from Hiroshima University, Japan. It did not study asbestos exposure. The authors examined miR-182 and miR-183, small RNA molecules that can turn down other genes. In stored mesothelioma tumor tissue, a staining method found miR-182 in 21 of 24 epithelioid and 4 of 5 sarcomatoid cases. It found miR-183 in all 24 epithelioid and all 5 sarcomatoid cases. In two lab-grown mesothelioma cell lines, blocking these molecules reduced cell growth, invasion, migration and attachment compared with a control treatment. Blocking both together gave the lowest migration. The exception was the miR-183 blocker alone in the ACC-MESO1 line, which did not significantly change invasion or migration. Blocking the molecules raised levels of a protein called FOXO1. Reducing FOXO1 levels reversed the drop in invasion and the rise in p27, but not the rise in p21. The authors concluded that miR-182 and miR-183 promote mesothelioma cell growth and invasion by targeting FOXO1. They said it remains to be clarified whether the effects on invasion, migration and attachment depend on cell growth.

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: in situ hybridization (staining) of archived human mesothelioma tissue, plus experiments on two mesothelioma cell lines treated with microRNA inhibitors and FOXO1 siRNA
• Who was studied: Archived formalin-fixed, paraffin-embedded tissue from 30 human mesothelioma patients at the Department of Pathology, Hiroshima University, Japan (results report 24 epithelioid and 5 sarcomatoid cases). Also two mesothelioma cell lines, ACC-MESO1 and CRL-5915. No dates given.
• Exposure: No asbestos exposure was studied. The experimental treatments were inhibitors of miR-182 and miR-183, alone or together, with or without FOXO1 siRNA, compared with negative control inhibitor or siRNA.
• Main results:
  • In human tissue, miR-182 was found in 21 of 24 epithelioid and 4 of 5 sarcomatoid mesothelioma cases. miR-183 was found in all 24 epithelioid and all 5 sarcomatoid cases.
  • In both cell lines, cells treated with the miR-182 or miR-183 inhibitor grew less than cells given the negative control inhibitor.
  • The miR-182 inhibitor significantly reduced invasion. Reductions in invasion and migration were significant (p less than 0.05) except for the miR-183 inhibitor alone in ACC-MESO1 cells.
  • Cells treated with both inhibitors together showed the lowest migration.
  • The inhibitors, alone or together, reduced the ability of mesothelioma cells to attach (adhere).
  • Treatment with the miR-182 and miR-183 inhibitors raised FOXO1 mRNA and protein levels.
  • Reducing FOXO1 levels with siRNA (knockdown) reversed the invasion-reducing effect of the inhibitors.
  • FOXO1 knockdown blocked the rise in p27 caused by the inhibitors, but not the rise in p21.
• The authors' conclusion: The authors concluded that miR-182 and miR-183 promote proliferation and invasion of mesothelioma cells by targeting FOXO1.
• Limitations the authors state:
  • The authors said more precise experiments are needed to clarify whether the effects on invasion, migration and adhesion are driven by the effects on proliferation.
  • The authors said the suppression of p21 by miR-182/183 needs further clarification.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

Related studies

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• PIM1 knockdown inhibits cell proliferation and invasion of mesothelioma cells — A.S. Mawas, V.J. Amatya, et al. (2017)
• Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1 — I. Endo, V.J. Amatya, et al. (2021)
• Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma — S. Wang, L. Jiang, et al. (2016)
• Downregulation of microRNA-34 induces cell proliferation and invasion of human mesothelial cells — N. Tanaka, S. Toyooka, et al. (2013)
• Critical role of the Ror-family of receptor tyrosine kinases in invasion and proliferation of malignant pleural mesothelioma cells — T. Saji, M. Nishita, et al. (2018)

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