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. 2022 Jun 2;12(1):9181.
doi: 10.1038/s41598-022-13044-0.

Dysregulation of microRNAs and tRNA-derived ncRNAs in mesothelial and mesothelioma cell lines after asbestiform fiber exposure

Veronica Filetti  1 , Alessandro La Ferlita  2   3 , Antonio Di Maria  2 , Venera Cardile  4 , Adriana C E Graziano  4 , Venerando Rapisarda  5 , Caterina Ledda  6 , Alfredo Pulvirenti #  2 , Carla Loreto #  1
Affiliations

Dysregulation of microRNAs and tRNA-derived ncRNAs in mesothelial and mesothelioma cell lines after asbestiform fiber exposure

Veronica Filetti et al. Sci Rep. .

Abstract

Experimental evidence demonstrated that fluoro-edenite (FE) can develop chronic respiratory diseases and elicit carcinogenic effects. Environmental exposure to FE fibers is correlated with malignant pleural mesothelioma (MPM). An early diagnosis of MPM, and a comprehensive health monitoring of the patients exposed to FE fibers are two clinical issues that may be solved by the identification of specific biomarkers. We reported the microRNA (miRNA) and transfer RNA-derived non coding RNA (tRNA-derived ncRNA) transcriptome in human normal mesothelial and malignant mesothelioma cell lines exposed or not exposed to several concentration FE fibers. Furthermore, an interactive mesothelioma-based network was derived by using NetME tool. In untreated condition, the expression of miRNAs and tRNA-derived ncRNAs in tumor cells was significantly different with respect to non-tumor samples. Moreover, interesting and significant changes were found after the exposure of both cells lines to FE fibers. The network-based pathway analysis showed several signaling and metabolic pathways potentially involved in the pathogenesis of MPM. From papers analyzed by NetME, it is clear that many miRNAs can positively or negatively influence various pathways involved in MPM. For the first time, the analysis of tRNA-derived ncRNAs molecules in the context of mesothelioma has been made by using in vitro systems. Further studies will be designed to test and validate their diagnostic potential in high-risk individuals' liquid biopsies.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Experimental workflow used to extract, process, and analyze RNA from cell lines.
Figure 2
Figure 2
Principal Component Analysis (PCA) showing a separation in miRNAs and tRNA-derived ncRNAs between: (A) JU77 (human malignant mesothelioma) vs. MeT-5A (human normal mesothelium) cell lines; (B) JU77 controls vs. exposed to 10 and 50 ug/ml FE fibers; (C) MeT-5A controls vs. exposed to 10 and 50 ug/ml FE fibers.
Figure 3
Figure 3
Volcano plots showing the differentially expressed miRNAs and tRNA-derived ncRNAs between: (A) JU77 (human malignant mesothelioma) vs. MeT-5A (human normal mesothelium); (B) Untreated vs. FE fibers treated JU77 and MeT-5A.
Figure 4
Figure 4
Venn diagrams showing down-regulated miRNAs and tRNA-derived ncRNAs distribution between: (A) JU77 vs. MeT-5A cell lines both not exposed and exposed to FE fibers; (C) The same cellular line both not exposed and exposed to FE fibers. Venn diagrams showing up-regulated miRNAs and tRNA-derived ncRNAs distribution between: (B) JU77 vs. MeT-5A cell lines both not exposed and exposed to FE fibers; (D) The same cellular line both not exposed and exposed to FE fibers.
Figure 5
Figure 5
Heatmap showing the dysregulated pathways in JU77 (human malignant mesothelioma) vs. MeT-5A (human normal mesothelium) at the same concentration of FE fibers exposure by taking into account the differentially expressed miRNAs.
Figure 6
Figure 6
Heatmap showing the dysregulated pathways between untreated vs. FE fibers treated JU77 (human malignant mesothelioma) and MeT-5A (human normal mesothelium) by taking into account the differentially expressed miRNAs.
Figure 7
Figure 7
Morphology of cells in confluent condition immortalized through Nikon microscope Eclipse Ts2 (magnification 10x), and morphology of single cells immortalized through FlowSight Imaging Flow Cytometer after no exposure, exposure to 10 ug/ml FE fibers, and exposure to 50 ug/ml FE fibers (magnification 20x) for: A) MeT-5A (human normal mesothelium); B) JU77 (human malignant mesothelioma).
Figure 8
Figure 8
(A) Dose–response curves of MeT-5A (human normal mesothelium) with FE fibers from 200 to 0.78 μg/ml until 72 h of treatments; (B) Dose–response curves of JU77 (human malignant mesothelioma) with FE fibers from 200 to 0.78 μg/ml from 6 to 72 h of treatments; (C) IC50 values (μg/ml) for MeT-5A and JU77 cell lines.
Figure 9
Figure 9
Mesothelioma-miRNAs network showing the relationships among pleural malignant mesothelioma disease and miRNAs derived from the PubMed Central full texts by using NetME tool. Such a network has been queried and displayed through Neo4j graph database and user interface.
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