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ASBESTOS INDUCES MESOTHELIAL CELL TRANSFORMATION VIA HMGB1-DRIVEN AUTOPHAGY
File under embargo until 2021-05-23
|Title:||ASBESTOS INDUCES MESOTHELIAL CELL TRANSFORMATION VIA HMGB1-DRIVEN AUTOPHAGY|
|Contributors:||Yang, Haining (advisor)|
Cell and Molecular Biology (department)
show 3 moreHMGB1
|Publisher:||University of Hawai'i at Manoa|
|Abstract:||Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as asbestos is toxic HM in cell culture. However, some asbestos-exposed HM escape cell death, where they accumulate DNA damage and may eventually become transformed. We have previously demonstrated that upon asbestos exposure, HM and reactive macrophages release the high mobility group box 1 (HMGB1) protein and trigger chronic inflammation. HMGB1 is commonly detected next to asbestos deposits in the staining of tissue biopsy. Also, serum HMGB1 is elevated in the sera of asbestos-exposed individuals and mice. While we seek for other serum biomarkers for early signs of asbestosis, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. This finding prompted us to continue to investigate the underlying mechanisms. We discovered that the release of HMGB1 upon asbestos exposure up-regulated autophagy, allowing an increased number of HM to survive asbestos toxicity. The HMGB1 silencing inhibited autophagy and promoted asbestos-induced HM death, therefore reducing the risk of asbestos-driven HM transformation. We demonstrated that autophagy was activated by the cytoplasmic and extracellular fractions of HMGB1 via the RAGE receptor and the Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial cell-specific 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 (CQ) and desmethylclomipramine (DCMI) increased cell death and reduced asbestos-led foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, which promotes HM survival and malignant transformation.|
|Rights:||All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.|
|Appears in Collections:||
Ph.D. - Cell and Molecular Biology|
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