Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats

Our plain-English summary of Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats, by Y. Okazaki, S.H. Chew, H. Nagai, et al (Cancer Science, 2020).

The study

• Authors: Y. Okazaki, S.H. Chew, H. Nagai, Y. Yamashita, H. Ohara, L. Jiang, S. Akatsuka, T. Takahashi, S. Toyokuni
• Journal: Cancer Science
• Published: 2020;111(6):2016-2027
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is one of the most lethal tumors in humans. The onset of MM is linked to exposure to asbestos, which generates reactive oxygen species (ROS). ROS are believed to be derived from the frustrated phagocytosis and the iron in asbestos. To explore the pathogenesis of MM, peritoneal MM was induced in rats by the repeated intraperitoneal injection of iron saccharate and nitrilotriacetate. In the present study, we used microarray techniques to screen the microRNA (miR) expression profiles of these MM. We observed that the histological subtype impacted the hierarchical clustering of miR expression profiles and determined that miR-199/214 is a distinctive feature of iron saccharate-induced sarcomatoid mesothelioma (SM). Twist1, a transcriptional regulator of the epithelial-mesenchymal transition, has been shown to activate miR-199/214 transcription; thus, the expression level of Twist1 was examined in iron-induced and asbestos-induced mesotheliomas in rats. Twist1 was exclusively expressed in iron saccharate-induced SM but not in the epithelioid subtype. The Twist1-miR-199/214 axis is activated in iron saccharate-induced and asbestos-induced SM. The expression levels of miR-214 and Twist1 were correlated in an asbestos-induced MM cell line, suggesting that the Twist1-miR-199/214 axis is preserved. MeT5A, an immortalized human mesothelial cell line, was used for the functional analysis of miR. The overexpression of miR-199/214 promoted cellular proliferation, mobility and phosphorylation of Akt and ERK in MeT5A cells. These results indicate that miR-199/214 may affect the aggressive biological behavior of SM.

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This was a laboratory study in rats and cultured cells. The authors studied mesotheliomas of the abdominal lining (peritoneal) caused in rats by repeated injections of iron saccharate and nitrilotriacetate. They also studied asbestos-induced rat tumor tissue, which the methods cite to an earlier study whose title names crocidolite, and asbestos-derived cell lines whose fiber this article does not state. They compared small regulatory molecules called microRNAs in four epithelioid and two sarcomatoid iron-induced tumors. Compared with the epithelioid tumors, the sarcomatoid tumors had 11.870-fold higher miR-214-3p, 9.398-fold higher miR-199a-5p and 8.528-fold higher miR-199a-3p. Twist1, a protein reported to switch on these microRNAs, was found in iron-induced sarcomatoid but not epithelioid tumors. It was also found in sarcomatoid parts of asbestos-induced biphasic tumors and in six asbestos-derived sarcomatoid cell lines. In the rat cell lines, Twist1 and miR-214 levels were correlated (P = 0.015). Adding miR-199/214 to a human mesothelial cell line, MeT5A, increased cell growth, cell movement, glutathione, and activation of the proteins Akt and ERK. The authors concluded that their results suggest this Twist1-miR-199/214 pathway plays an essential role in sarcomatoid mesothelioma.

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: Animal and laboratory study: microRNA microarray profiling of rat mesothelioma tissue, with tissue staining, protein tests, and cell-culture experiments in a human mesothelial cell line
• Who was studied: Rat (Fischer344 x Brown-Norway hybrid) tumor samples. The microarray used 4 epithelioid and 2 sarcomatoid iron-induced mesotheliomas plus 2 non-cancerous mesothelial cell samples. The study also used asbestos-induced rat tumor tissue, rat mesothelioma cell lines from bloody ascites (fluid in the abdomen), and the immortalized human mesothelial cell line MeT5A.
• Exposure: Intraperitoneal (into the abdomen) injection of ferric saccharate and nitrilotriacetate. The study also used asbestos-induced mesothelioma tissue, which the methods cite to an earlier study whose title refers to crocidolite-induced mesothelial carcinogenesis in rats. The fiber type for the asbestos-derived cell lines is not stated in this article. In the cell work, MeT5A cells were made to overexpress miR-199/214.
• Main results:
  • MicroRNA patterns clearly differed among epithelioid tumors, sarcomatoid tumors and non-cancerous mesothelial cells.
  • In iron-induced sarcomatoid versus epithelioid tumors, miR-214-3p was upregulated 11.870-fold (P = 0.0032). In the same comparison, miR-199a-5p was up 9.398-fold (P = 0.0018) and miR-199a-3p 8.528-fold (P = 0.0005).
  • Tissue staining for miR-214-3p gave a stronger signal in sarcomatoid than in epithelioid tumors.
  • The miR-200 family was downregulated in sarcomatoid tumors; for example, the table lists rno-miR-200a-3p with a fold change of 1932.964 (P = 0.0007).
  • Twist1 protein built up in the cell nuclei of iron-induced sarcomatoid tumors but not epithelioid tumors.
  • In asbestos-induced tumors, Twist1 was found in sarcomatoid tumors and in sarcomatoid components of biphasic mesothelioma, but not in epithelial components.
  • Rat mesothelioma cell lines from asbestos-induced bloody ascites showed high Twist1 in six sarcomatoid lines. In these cell lines, Twist1 and miR-214 levels were correlated (Fisher's exact test, P = 0.015). Only two of the six sarcomatoid lines showed significant elevation of miR-199-3p.
  • In MeT5A cells, overexpressing miR-199/214 increased cell proliferation and colony formation without changing cell shape. It also increased cell movement.
  • In MeT5A cells, overexpressing miR-199/214 increased cellular glutathione at days 2 and 3.
  • In MeT5A cells, miR-199/214 significantly increased phospho-Akt and phospho-ERK (activated forms of these proteins). PTEN was unchanged and phospho-p38 was not significantly altered.
• The authors' conclusion: The authors concluded that miR-199/214 is overexpressed in iron saccharate-induced sarcomatoid mesothelioma in rats, is associated with Twist1, and promotes cell proliferation and migration. They wrote that the results suggest the Twist1-miR-199/214 axis plays an essential role in sarcomatoid mesothelioma.
• Limitations the authors state:
  • The authors stated that further study may be needed to tell apart effects started by Twist1 from effects started by miR-199/214.
  • Twist1 and miR-199-3p levels did not match in all sarcomatoid cell lines. The authors suggested that another mechanism might regulate miR-199.

Topics

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

Medical terms in this study, explained in our Lexicon: Sarcomatoid, Mesothelioma, Malignant Mesothelioma, Reactive Oxygen Species (ROS), Frustrated Phagocytosis, Histological Subtype, Epithelioid, Mesothelial Cells.

Related studies

• Iron overload signature in chrysotile-induced malignant mesothelioma — L. Jiang, S. Akatsuka, et al. (2012)
• Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer — S. Akatsuka, Y. Yamashita, et al. (2012)
• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)
• Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma — L. Jiang, Y. Yamashita, et al. (2014)
• Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis — L. Jiang, S.H. Chew, et al. (2016)
• Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice — S. Funahashi, Y. Okazaki, et al. (2018)

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