ADAR2 Regulates Malignant Behaviour of Mesothelioma Cells Independent of RNA-editing Activity

Our plain-English summary of ADAR2 Regulates Malignant Behaviour of Mesothelioma Cells Independent of RNA-editing Activity, by K.I. Sakata, K. Maeda, N. Sakurai, et al (Anticancer Research, 2020).

The study

• Authors: K.I. Sakata, K. Maeda, N. Sakurai, S. Liang, S. Nakazawa, K. Yanagihara, T. Kubo, H. Yoshiyama, Y. Kitagawa, J.I. Hamada, H. Iizasa
• Journal: Anticancer Research
• Published: 2020;40(3):1307-1314
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background/aim: Malignant pleural mesothelioma (MPM) is an intractable cancer, and causes of its malignant transformation are not well known. Adenosine deaminase acting on RNA (ADAR) is an RNA-editing enzyme that converts adenosine into inosine in double-stranded RNAs potentially involved in malignant development.

Materials And Methods: To examine the role of ADAR1 and ADAR2 in MPM, small interfering RNAs (siRNAs) against ADAR1 or ADAR2 were used.

Results: Transfection of siRNA against ADAR2 suppressed proliferation, motility, and invasiveness of MPM cells expressing both ADAR1 and ADAR2; however, siRNA against ADAR1 did not affect these cellular activities. Overexpression of ADAR2, that was incapable of binding to RNA, suppressed growth, motility, and invasion of MPM cells. However, overexpression of ADAR2 that had no enzyme activity did not alter the malignant properties of MPM cells.

Conclusion: Enhancement of the malignant characteristics of cultured MPM cells via ADAR2 was independent of RNA-editing activity.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

In plain English

This was a laboratory study of human malignant pleural mesothelioma (MPM) cells grown in culture. It did not study asbestos exposure or patients. The authors examined two RNA-editing enzymes, ADAR1 and ADAR2. All six mesothelioma cell lines tested expressed both enzymes. In one cell line, TCC-MESO-1, the authors used small interfering RNAs to lower each enzyme's levels. This cut ADAR2 messenger RNA by 53% compared with control cells. Lowering ADAR2 reduced the cells' growth, movement and invasion into collagen gels, while lowering ADAR1 did not. The authors then added altered forms of ADAR2 to the cells. Normal ADAR2, and a form that can bind RNA but cannot edit it, did not change growth, movement or invasion. A form that cannot bind RNA reduced growth by 36% and also reduced movement and invasion. The authors concluded that ADAR2 promoted growth, motility and invasion of these cells independently of its RNA-editing activity, and that investigating ADAR2 as a treatment target may be promising. They noted it remains unclear whether these cells contain ADAR2 targets other than COPA.

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) experiment on cultured human mesothelioma cell lines
• Who was studied: Six human malignant pleural mesothelioma cell lines (TCC-MESO-1, TCC-MESO-2, TCC-MESO-3, HMM1, HMM3 and NCI-H226). Five were established from primary and metastatic tumours of MPM patients. Most experiments used TCC-MESO-1.
• Exposure: No asbestos exposure was studied. The cells were treated with small interfering RNAs to lower ADAR1 or ADAR2, or given normal ADAR2 or mutant forms (T375A, which cannot edit RNA; EAA, which cannot bind RNA).
• Main results:
  • All six cell lines expressed both ADAR1 and ADAR2.
  • In TCC-MESO-1 cells, ADAR2 siRNA lowered ADAR2 mRNA by 53% compared with control cells.
  • In TCC-MESO-1 cells, ADAR1 siRNAs lowered ADAR1 mRNA by up to 80% when both were combined.
  • Lowering ADAR2, but not ADAR1, inhibited cell proliferation.
  • Lowering ADAR2, but not ADAR1, inhibited invasion of TCC-MESO-1 cells into type I collagen gels.
  • Lowering ADAR2 significantly reduced cell motility. ADAR1 siRNAs did not alter motility.
  • Neither mutant ADAR2 (T375A or EAA) produced COPA mRNA editing in TCC-MESO-1 cells.
  • Normal (wild-type) ADAR2 and the T375A mutant did not affect proliferation of TCC-MESO-1 cells.
  • The EAA mutant (unable to bind RNA) significantly reduced proliferation of TCC-MESO-1 cells, by 36%.
  • The EAA mutant significantly decreased motility and invasion compared with control cells. Wild-type ADAR2 and T375A left these properties unaffected.
• The authors' conclusion: The authors concluded that ADAR2 promoted growth, motility and invasion of MPM cells independently of its RNA-editing activity, and that investigating ADAR2 as a novel therapeutic target for MPM may be promising.
• Limitations the authors state:
  • The authors stated it remains unclear whether ADAR2-specific substrates other than COPA are present in MPM cells.
  • The authors stated that functions of ADAR2 other than RNA editing are not well understood.

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: Mesothelioma, Pleural Mesothelioma, Malignant Transformation.

Related studies

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• RNA editing in mesothelioma: a look forward — A. Hariharan, S. Sun, et al. (2020)
• How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations — H. Rehrauer, L. Wu, et al. (2018)
• Adenosine deaminase inhibitor EHNA exhibits a potent anticancer effect against malignant pleural mesothelioma — Y. Nakajima, T. Kanno, et al. (2015)
• The small GTPase RhoA regulates the expression and function of the sodium channel Nav1.5 in breast cancer cells — C. Dulong, Y.J. Fang, et al. (2014)
• Adenosine diphosphate regulates MMP2 and MMP9 activity in malignant mesothelioma cells — A. Muscella, L.G. Cossa, et al. (2018)

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