Continuous Exposure to Chrysotile Asbestos Can Cause Transformation of Human Mesothelial Cells via HMGB1 and TNF-α Signaling
Continuous Exposure to Chrysotile Asbestos Can Cause Transformation of Human Mesothelial Cells via HMGB1 and TNF-α Signaling
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DOI：
10.1016/j.ajpath.2013.07.029
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发表时间：
2013-11-01
影响因子：
6
通讯作者：
Carbone, Michele
中科院分区：
文献类型：
--
作者：
Qi, Fang;Okimoto, Gordon;Carbone, Michele
恶性间皮瘤与石棉暴露密切相关。在石棉纤维中，青石棉的致癌性最高，温石棉的致癌性最低。温石棉占全球使用的石棉的90%以上，但其诱发恶性间皮瘤的能力仍有争议。我们发现温石棉和青石棉暴露对人类间皮细胞有类似的影响。形态学和分子变化提示上皮间质转化，如E-钙粘蛋白下调和β-连环蛋白磷酸化，然后核转位，诱导温石棉和青石棉。基因表达谱显示高迁移率族蛋白-1（HMGB 1）是两种石棉诱导的转录改变的关键调节因子。青石棉和温石棉诱导的差异表达的28,869个基因中的438寡核苷酸芯片询问。在这438个基因中，57个与炎症和免疫反应以及癌症相关，14个是HMGB 1靶向基因。青石棉诱导的基因改变持续，而温石棉诱导的基因改变在5周内恢复到背景水平。同样，在青石棉暴露后10周或更长时间内，体内HMGB 1的释放逐渐增加，但在温石棉暴露后8周内恢复到背景水平。持续高血清HMGB 1水平需要持续给予温石棉。这些数据支持了生物持久性的差异影响这两种石棉纤维的生物活性的假设。
Malignant mesothelioma is strongly associated with asbestos exposure. Among asbestos fibers, crocidolite is considered the most and chrysotile the Least oncogenic. Chrysotile accounts for more than 90% of the asbestos used worldwide, but its capacity to induce malignant mesothelioma is still debated. We found that chrysotile and crocidolite exposures have similar effects on human mesothelial cells. Morphological and molecular alterations suggestive of epithelial mesenchymal transition, such as E-cadherin down-regulation and beta-catenin phosphorylation followed by nuclear translocation, were induced by both chrysotile and crocidolite. Gene expression profiling revealed high-mobility group box-1 protein (HMGB1) as a key regulator of the transcriptional alterations induced by both types of asbestos. Crocidolite and chrysotile induced differential expression of 438 out of 28,869 genes interrogated by oligonucleotide microarrays. Out of these 438 genes, 57 were associated with inflammatory and immune response and cancer, and 14 were HMGB1 targeted genes. Crocidolite-induced gene alterations were sustained, whereas chrysotile-induced gene alterations returned to background levels within 5 weeks. Similarly, HMGB1 release in vivo progressively increased for 10 or more weeks after crocidolite exposure, but returned to background levels within 8 weeks after chrysotile exposure. Continuous administration of chrysotite was required for sustained high serum levels of HMGB1. These data support the hypothesis that differences in biopersistence influence the biological activities of these two asbestos fibers.