<scp>BRCA1</scp> haploinsufficiency impairs iron metabolism to promote chrysotile‐induced mesothelioma via ferroptosis resistance
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- Yaguang Luo
- Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine Nagoya Japan
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- Shinya Akatsuka
- Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine Nagoya Japan
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- Yashiro Motooka
- Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine Nagoya Japan
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- Yingyi Kong
- Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine Nagoya Japan
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- Hao Zheng
- Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine Nagoya Japan
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- Tomoji Mashimo
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science The University of Tokyo Tokyo Japan
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- Tatsuhiko Imaoka
- Department of Radiation Effects Research, National Institute of Radiological Sciences National Institutes for Quantum Science and Technology Chiba Japan
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- Shinya Toyokuni
- Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine Nagoya Japan
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説明
<jats:title>Abstract</jats:title><jats:p>Malignant mesothelioma (MM) is still a social burden associated with asbestos exposure. Local iron accumulation thereby represents the major pathogenesis, followed by oxidative DNA strand breaks and genomic alterations in the mesothelium. BRCA1 is a critical component of homologous recombination repair directed to DNA double‐stranded breaks, whereas <jats:italic>BRCA1</jats:italic> germline mutation is an established risk for breast/ovarian cancer, its role in MM development remains to be elucidated. Murine <jats:italic>Brca1</jats:italic> mutant models so far have not reproduced human phenotypes. However, a rat <jats:italic>Brca1</jats:italic> mutant model (Mut; L63X/+ ) recently reproduced them at least partially. Here we describe the differential induction of MM in <jats:italic>Brca1</jats:italic> mutant rats by intraperitoneal injection of chrysotile or crocidolite. Only Mut males injected with chrysotile revealed a promotional effect on mesothelial carcinogenesis in comparison with wild‐type and/or females, with all the MMs <jats:italic>Brca1</jats:italic> haploinsufficient. Array‐based comparative genomic hybridization of MMs disclosed a greater extent of chromosomal deletions in <jats:italic>Brca1</jats:italic> mutants, including <jats:italic>Cdkn2a</jats:italic>/<jats:italic>2b</jats:italic> accompanied by <jats:italic>Tfr2</jats:italic> amplification, in comparison with wild‐type tumors. Mutant MMs indicated iron metabolism dysregulation, such as an increase in catalytic Fe(II) and Ki67‐index as well as a decrease in Fe(III) and ferritin expression. Simultaneously, mutant MMs revealed ferroptosis resistance by upregulation of Slc7A11 and Gpx4. At an early carcinogenic stage of 4 weeks, induced Brca1 expression in mesothelial cells was significantly suppressed in chrysotile/Mut in comparison with crocidolite/Mut, whereas significant preference to iron with a decrease in Fe(III) has been already established. In conclusion, chrysotile exposure can be a higher risk for MM in <jats:italic>BRCA1</jats:italic> mutant males, considering the rat results.</jats:p>
収録刊行物
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- Cancer Science
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Cancer Science 114 (4), 1423-1436, 2023-02-02
Wiley