Department of Occupational Health & Radiation Hygiene, Hangzhou Hospital for the Prevention and Treatment of Occupational Disease, Hangzhou, Zhejiang, China.
School of Public Heath, Hangzhou Medical College, Hangzhou, Zhejiang, China.
J Environ Sci Health C Toxicol Carcinog. 2023;41(3-4):121-134. doi: 10.1080/26896583.2023.2271822. Epub 2023 Dec 13.
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) and Met-5A were estimated to be 0.71 μg/cm and 1.8 μg/cm, 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 (chronical Cro-Met-5A) 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. Chronical Cro-Met-5A 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 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, 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.
青石棉是一种致癌物质，可导致恶性间皮瘤的发病机制。本研究旨在研究在青石棉暴露下，有和没有 SETD2 的间皮细胞发生恶性转化的可能与端粒相关的事件。在 72 小时的暴露中，导致 SETD2 敲除 Met-5A（Met-5A）和 Met-5A 存活率达到 90%的青石棉浓度分别估计为 0.71μg/cm 和 1.8μg/cm，在接下来的一个月内，每 72 小时暴露一次，持续暴露于青石棉。与慢性青石棉暴露的 Met-5A（chronic Cro-Met-5A）相比，慢性青石棉暴露的 Met-5A（chronic Cro-Met-5A）具有更高的集落形成能力和更高的端粒酶逆转录酶（TERT）蛋白水平。与慢性青石棉暴露的 Met-5A 相比，chronic Cro-Met-5A 的端粒长度（TL）更长，尽管与未暴露于青石棉的相应细胞相比，chronic Cro-Met-5A 或 chronic Cro-Met-5A 的 TL 没有变化。靶向 TERT 的抑制剂 BIBR 1532 部分减少了 chronic Cro-Met-5A 的集落形成和 TL，而 BIBR 1532 降低了 TL，但对 chronic Cro-Met-5A 的集落形成没有影响。因此，在慢性青石棉暴露期间，SETD2 缺陷的间皮细胞易发生恶性转化，而 TERT 依赖性 TL 修饰可能部分驱动 SETD2 缺失介导的间皮恶性转化的早期发生。
