Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy.

Authors: Xue, Jiaming; Patergnani, Simone; Giorgi, Carlotta; Suarez, Joelle; Goto, Keisuke; Bononi, Angela; Tanji, Mika; Novelli, Flavia; Pastorino, Sandra; Xu, Ronghui; Caroccia, Natascia; Dogan, A Umran; Pass, Harvey I; Tognon, Mauro; Pinton, Paolo; Gaudino, Giovanni; Mak, Tak W; Carbone, Michele; Yang, Haining

Published In Proc Natl Acad Sci U S A, (2020 10 13)

Abstract: Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation.

PubMed ID: 32999071 Exiting the NIEHS site

MeSH Terms: Adult; Aged; Animals; Asbestos/adverse effects*; Autophagy/drug effects*; Cell Transformation, Neoplastic/chemically induced*; Cells, Cultured; Epithelial Cells/cytology; Epithelial Cells/metabolism; HMGB1 Protein/metabolism*; Humans; Male; Mesothelioma/metabolism*; Mice; Mice, Knockout; Middle Aged; Occupational Exposure

Back
to Top