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Mesothelioma: Identification of the Key Molecular Events Triggered by BAP1

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Technical Report,15 Aug 2013,31 Jan 2016

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University of Hawaii Systems Honolulu United States

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We discovered that germline BAP1 mutations cause a novel cancer syndrome characterized by a very high incidence of malignant mesothelioma MM. We have conducted a number of in vitro and in vivo experiments to study the mechanism s during the two years and obtained exciting results. We found that BAP1 status regulate NF-kB activity and HMGB1 release. BAP1 silenced HM cells and macrophages release more HMGB1 into the extra cellular space, which suggests that germline BAP1 mutations by increasing the release of HMGB1 create an environment favorable to malignant transformation. Moreover, we found that BAP1 silenced HM cells are much less sensitive to asbestos induced cytotoxicity, and that BAP1 silenced HMcells form significantly more foci in tissue culture compared to cells containing wild type BAP1. Together these in vitro studies suggested that germline BAP1 mutations would increase susceptibility to asbestos carcinogenesis, which was further proven correct in the animal experiments. We found that BAP1 - mice develop more MMs and had shorter survival probably related to earlier tumor development compared to wild type littermates. BAP1 loss increased the susceptibility to low doses of asbestos that rarely cause MM in animals carrying wild type BAP1. Moreover, we linked the increased susceptibility of BAP1 - mice to asbestos carcinogenicity to differences in the chronic inflammatory response, and to the release of specific cytokines and chemokines that follows asbestos exposure in BAP1 - mice.

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  • Medicine and Medical Research

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