Continuous Exposure to Chrysotile Asbestos Can Cause Transformation of Human Mesothelial Cells via HMGB1 and TNF-α Signaling

• Published in: The American journal of pathology Vol. 183; no. 5; pp. 1654 - 1666
• Main Authors: Qi, Fang, Okimoto, Gordon, Jube, Sandro, Napolitano, Andrea, Pass, Harvey I, Laczko, Rozalia, DeMay, Richard M, Khan, Ghazal, Tiirikainen, Maarit, Rinaudo, Caterina, Croce, Alessandro, Yang, Haining, Gaudino, Giovanni, Carbone, Michele
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2013; American Society for Investigative Pathology
• Subjects: Animals; Asbestos, Crocidolite - toxicity; Asbestos, Serpentine - toxicity; beta Catenin - metabolism; Cadherins - metabolism; Cell Death - drug effects; Cell Line; Cell Shape - drug effects; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Epithelium - drug effects; Epithelium - metabolism; Epithelium - pathology; Gene Expression Profiling; Gene Expression Regulation - drug effects; Genome, Human - genetics; HMGB1 Protein - blood; HMGB1 Protein - metabolism; HMGB1 Protein - secretion; Humans; Mice; Pathology; Regular; Signal Transduction - drug effects; Signal Transduction - genetics; Transcription, Genetic - drug effects; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2013.07.029

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 β-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 chrysotile 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.