Characteristics of transcription profile, adhesion and migration of SETD2‐loss Met‐5A mesothelial cells exposed with crocidolite.

Asbestos is a fibrous silicate mineral exhibiting biopersistence and carcinogenic properties and contributes to mesothelioma. Despite the concept of gene‐environmental interaction in pathogenesis of mesothelioma, the possible pathophysiological changes of mesothelial cells simultaneously with SET domain containing 2 (SETD2) loss and asbestos exposure remains obscure. Herein, CRISPR/Cas9‐mediated SETD2 knockout Met‐5A mesothelial cells (Met‐5ASETD2‐KO) were established and exposed with crocidolite, an amphibole asbestos. Cell viability of Met‐5ASETD2‐KO appeared to dramatically decrease with ≥2.5 μg/cm2 crocidolite exposure as compared with Met‐5A, although no cytotoxicity and apoptosis changes of Met‐5ASETD2‐KO and Met‐5A was evident with 1.25 μg/cm2 crocidolite exposure for 48 h. RNA sequencing uncovered top 50 differentially expressed genes (DEGs) between 1.25 μg/cm2 crocidolite exposed Met‐5ASETD2‐KO (Cro‐Met‐5ASETD2‐KO) and 1.25 μg/cm2 crocidolite exposed Met‐5A (Cro‐Met‐5A), and ITGA4, THBS2, MYL7, RAC2, CADM1, and CLDN11 appeared to be the primary DEGs involved with adhesion in gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Cro‐Met‐5ASETD2‐KO had strong migration but mild adhesion behavior as compared with Cro‐Met‐5A. Additionally, crocidolite tended to increase migration of Met‐5ASETD2‐KO but inhibited migration of Met‐5A when compared with their corresponding cells without crocidolite exposure, although no further adhesion property changes was evident for both cells in response to crocidolite. Therefore, crocidolite may affect adhesion‐related gene expression and modify adhesion and migration behavior for SETD2‐depleted Met‐5A, which could provide preliminary insight regarding the potential role of SETD2 in the cell behavior of asbestos‐related malignant mesothelial cell. Gene‐environmental interaction might drive pathophysiological changes in mesothelium and mesothelioma raised by asbestos. The established SETD2 depleted Met‐5A underwent non‐cytotoxic dosage of crocidolite exposure and exhibited six differentially expressed genes primarily involved with adhesion function, resulting in enhanced migration and delayed adhesion property, which may provide preliminary insights regarding the potential role of SETD2 loss in asbestos‐related mesothelium abnormality. [ABSTRACT FROM AUTHOR]