Mesothelioma: Identification of the Key Molecular Events Triggered by BAP1
Abstract
We discovered that germline BAP1 mutations cause a novel cancer syndrome characterized by a very high incidence of malignant mesothelioma (MM). In order to study the mechanism(s), we have conducted a number of in vitro and in vivo experiments and obtained very good results. We found that BAP1 silenced HM cells (and macrophages) release more HMGB1into the extra cellular space. These in vitro findings suggested that germline BAP1 mutations by increasing the release ofHMGB1 create an environment favorable to malignant transformation. Moreover, we found that BAP1 silenced HM cells are much less sensitive to asbestos induced cytotoxicity compared to cells with wild type BAP1, and a larger pool of cells survives asbestos exposure increasing the probability of malignant transformation. Accordingly we found that BAP1 silenced HM cells exposed to asbestos 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, an hypothesis that we tested in Aim 3 in mice and that was proven correct. We found that BAP1+/- mice develop more MMs and had shorter survival (probably related to earlier tumor development) compared to wild type littermates. Moreover, BAP1 loss increased the susceptibility to low doses of asbestos that rarely cause MM in animals carrying wild type BAP1. Mechanistically, 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2015
- Accession Number
- AD1011712
Entities
People
- Haining Yang
Organizations
- University of Hawaiʻi System