Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFR L858R -lung cancer mice
Abstract Tumor heterogeneity is the major factor for inducing drug resistance. p53 is the major defender to maintain genomic stability, which is a high proportion mutated in most of the cancer types. In this study, we established in vivo animal models of gefitinib-induced drug-resistant lung cancer...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-03-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01393-2 |
| _version_ | 1797865568283394048 |
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| author | Yi-Shiang Wang Ming-Jer Young Chia-Yu Liu Yung-Ching Chen Jan-Jong Hung |
| author_facet | Yi-Shiang Wang Ming-Jer Young Chia-Yu Liu Yung-Ching Chen Jan-Jong Hung |
| author_sort | Yi-Shiang Wang |
| collection | DOAJ |
| description | Abstract Tumor heterogeneity is the major factor for inducing drug resistance. p53 is the major defender to maintain genomic stability, which is a high proportion mutated in most of the cancer types. In this study, we established in vivo animal models of gefitinib-induced drug-resistant lung cancer containing EGFR L858R and EGFR L858R *Tp53 +/− mice to explore the molecular mechanisms of drug resistance by studying the genomic integrity and global gene expression. The cellular morphology of the lung tumors between gefitinib-induced drug-resistant mice and drug-sensitive mice were very different. In addition, in drug-resistant mice, the expression of many cytoskeleton-related genes were changed, accompanied by decreased amounts of actin filaments and increased amounts of microtubule, indicating that significant cytoskeletal remodeling is induced in gefitinib-induced drug-resistant EGFR L858R and EGFR L858R *Tp53 +/− lung cancer mice. The gene expression profiles and involved pathways were different in gefitinib-sensitive, gefitinib-resistant and Tp53 +/− -mice. Increases in drug resistance and nuclear size (N/C ratio) were found in EGFR L858R *Tp53 +/− drug-resistant mice. Mutational hotspot regions for drug resistance via Tp53 +/+ - and Tp53 +/− -mediated pathways are located on chromosome 1 and chromosome 11, respectively, and are related to prognosis of lung cancer cohorts. This study not only builds up a gefitinib-induced drug-resistant EGFR L858R lung cancer animal model, but also provides a novel mutation profile in a Tp53 +/+ - or Tp53 +/− -mediated manner and induced cytoskeleton remodeling during drug resistance, which could contribute to the prevention of drug resistance during cancer therapy. |
| first_indexed | 2024-04-09T23:11:18Z |
| format | Article |
| id | doaj.art-d7ed534d60404f2d8d06f4ca0187b6d8 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-09T23:11:18Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-d7ed534d60404f2d8d06f4ca0187b6d82023-03-22T10:25:55ZengNature Publishing GroupCell Death Discovery2058-77162023-03-019111310.1038/s41420-023-01393-2Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFR L858R -lung cancer miceYi-Shiang Wang0Ming-Jer Young1Chia-Yu Liu2Yung-Ching Chen3Jan-Jong Hung4Institute of Basic Medical Sciences, National Cheng Kung UniversityDepartment of Biotechnology and Bioindustry Sciences, National Cheng Kung UniversityDepartment of Biotechnology and Bioindustry Sciences, National Cheng Kung UniversityDepartment of Biotechnology and Bioindustry Sciences, National Cheng Kung UniversityInstitute of Basic Medical Sciences, National Cheng Kung UniversityAbstract Tumor heterogeneity is the major factor for inducing drug resistance. p53 is the major defender to maintain genomic stability, which is a high proportion mutated in most of the cancer types. In this study, we established in vivo animal models of gefitinib-induced drug-resistant lung cancer containing EGFR L858R and EGFR L858R *Tp53 +/− mice to explore the molecular mechanisms of drug resistance by studying the genomic integrity and global gene expression. The cellular morphology of the lung tumors between gefitinib-induced drug-resistant mice and drug-sensitive mice were very different. In addition, in drug-resistant mice, the expression of many cytoskeleton-related genes were changed, accompanied by decreased amounts of actin filaments and increased amounts of microtubule, indicating that significant cytoskeletal remodeling is induced in gefitinib-induced drug-resistant EGFR L858R and EGFR L858R *Tp53 +/− lung cancer mice. The gene expression profiles and involved pathways were different in gefitinib-sensitive, gefitinib-resistant and Tp53 +/− -mice. Increases in drug resistance and nuclear size (N/C ratio) were found in EGFR L858R *Tp53 +/− drug-resistant mice. Mutational hotspot regions for drug resistance via Tp53 +/+ - and Tp53 +/− -mediated pathways are located on chromosome 1 and chromosome 11, respectively, and are related to prognosis of lung cancer cohorts. This study not only builds up a gefitinib-induced drug-resistant EGFR L858R lung cancer animal model, but also provides a novel mutation profile in a Tp53 +/+ - or Tp53 +/− -mediated manner and induced cytoskeleton remodeling during drug resistance, which could contribute to the prevention of drug resistance during cancer therapy.https://doi.org/10.1038/s41420-023-01393-2 |
| spellingShingle | Yi-Shiang Wang Ming-Jer Young Chia-Yu Liu Yung-Ching Chen Jan-Jong Hung Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFR L858R -lung cancer mice Cell Death Discovery |
| title | Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFR L858R -lung cancer mice |
| title_full | Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFR L858R -lung cancer mice |
| title_fullStr | Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFR L858R -lung cancer mice |
| title_full_unstemmed | Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFR L858R -lung cancer mice |
| title_short | Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFR L858R -lung cancer mice |
| title_sort | tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib induced drug resistant egfr l858r lung cancer mice |
| url | https://doi.org/10.1038/s41420-023-01393-2 |
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