{"title":"Effects of SETD2 on telomere length and malignant transformation property of Met-5A after one-month crocidolite exposure.","authors":"Min Yu, Dan Yang, Chiyun Chen, Hailing Xia","doi":"10.1080/26896583.2023.2271822","DOIUrl":null,"url":null,"abstract":"<p><p>Crocidolite is a carcinogen contributing to the pathogenesis of malignant mesothelioma. This study aimed to characterize the possible telomere-related events mediating the malignant transformation of mesothelial cells with and without SETD2 under crocidolite exposure. The crocidolite concentration resulting in 90% viable SETD2 knockout Met-5A (Met-5A<sup>SETD2-KO</sup>) and Met-5A were estimated to be 0.71 μg/cm<sup>2</sup> and 1.8 μg/cm<sup>2</sup>, respectively, during 72 h of exposure, which was further employed in chronical crocidolite exposure during a 72 h exposure interval per time up to 1 month. Chronical crocidolite-exposed Met-5A<sup>SETD2-KO</sup> (chronical Cro-Met-5A<sup>SETD2-KO</sup>) had higher colony formation and increased telomerase reverse transcriptase (TERT) protein levels than chronical crocidolite-exposed Met-5A (chronical Cro-Met-5A) and Met-5A<sup>SETD2-KO</sup>. Chronical Cro-Met-5A<sup>SETD2-KO</sup> had longer telomere length (TL) than chronical Cro-Met-5A, although there were no changes in TL for either chronical Cro-Met-5A or chronical Cro-Met-5A<sup>SETD2-KO</sup> compared with their corresponding cells without crocidolite exposure. BIBR 1532, an inhibitor targeting TERT, partially reduced colony formation and TL for chronical Cro-Met-5A<sup>SETD2-KO</sup>, while BIBR 1532 reduced TL but had no effect on colony formation for chronical Cro-Met-5A. Therefore, SETD2 deficient mesothelial cells are susceptible to malignant transformation during chronical crocidolite exposure, and TERT-dependent TL modification likely partially drives SETD2 loss-mediated early onset of mesothelial malignant transformation.</p>","PeriodicalId":53200,"journal":{"name":"Journal of Environmental Science and Health Part C-Toxicology and Carcinogenesis","volume":" ","pages":"121-134"},"PeriodicalIF":1.2000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Environmental Science and Health Part C-Toxicology and Carcinogenesis","FirstCategoryId":"93","ListUrlMain":"https://doi.org/10.1080/26896583.2023.2271822","RegionNum":4,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/12/13 0:00:00","PubModel":"Epub","JCR":"Q4","JCRName":"ENVIRONMENTAL SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Crocidolite is a carcinogen contributing to the pathogenesis of malignant mesothelioma. This study aimed to characterize the possible telomere-related events mediating the malignant transformation of mesothelial cells with and without SETD2 under crocidolite exposure. The crocidolite concentration resulting in 90% viable SETD2 knockout Met-5A (Met-5ASETD2-KO) and Met-5A were estimated to be 0.71 μg/cm2 and 1.8 μg/cm2, respectively, during 72 h of exposure, which was further employed in chronical crocidolite exposure during a 72 h exposure interval per time up to 1 month. Chronical crocidolite-exposed Met-5ASETD2-KO (chronical Cro-Met-5ASETD2-KO) had higher colony formation and increased telomerase reverse transcriptase (TERT) protein levels than chronical crocidolite-exposed Met-5A (chronical Cro-Met-5A) and Met-5ASETD2-KO. Chronical Cro-Met-5ASETD2-KO had longer telomere length (TL) than chronical Cro-Met-5A, although there were no changes in TL for either chronical Cro-Met-5A or chronical Cro-Met-5ASETD2-KO compared with their corresponding cells without crocidolite exposure. BIBR 1532, an inhibitor targeting TERT, partially reduced colony formation and TL for chronical Cro-Met-5ASETD2-KO, while BIBR 1532 reduced TL but had no effect on colony formation for chronical Cro-Met-5A. Therefore, SETD2 deficient mesothelial cells are susceptible to malignant transformation during chronical crocidolite exposure, and TERT-dependent TL modification likely partially drives SETD2 loss-mediated early onset of mesothelial malignant transformation.