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

Cancer Sci. 2020 Jun;111(6):2016-2027. doi: 10.1111/cas.14405. Epub 2020 May 5.

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.

Keywords: Twist1; animal model; asbestos; iron-induced mesothelioma; miR-199/214.

MeSH terms

  • Animals
  • Asbestos / toxicity
  • Cell Line
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Iron / toxicity
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Mesothelioma / genetics
  • Mesothelioma / metabolism
  • Mesothelioma / pathology*
  • Mesothelioma, Malignant
  • MicroRNAs / biosynthesis*
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / pathology*
  • Rats
  • Twist-Related Protein 1 / biosynthesis*

Substances

  • MIRN199 microRNA, rat
  • MIRN214 microRNA, human
  • MicroRNAs
  • Mirn214 microRNA,rat
  • Twist-Related Protein 1
  • mirn199 microRNA, human
  • Asbestos
  • Iron