PLoS genetics, 2020-01, Vol.16 (1), p.e1008558
2020
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- Autor(en) / Beteiligte
- Titel
- Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors
- Ist Teil von
- PLoS genetics, 2020-01, Vol.16 (1), p.e1008558
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2020
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Autophagy, particularly with BECN1, has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1+/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1+/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7404, 1553-7390eISSN: 1553-7404DOI: 10.1371/journal.pgen.1008558Titel-ID: cdi_plos_journals_2355995884
- Format
- –
- Schlagworte
- Animals, Antigens, Autophagy, Beclin-1 - genetics, Biochemistry, Biology and Life Sciences, BRCA1 protein, Breast, Breast cancer, Cancer cells, Cancer genetics, Cancer research, Carcinogenesis, Carcinogenesis - genetics, Cell death, Cell Line, Tumor, Cell Movement, Chromatography, Chromosomal Instability, Chromosome 11, Chromosome 17, Chromosomes, Clonal deletion, Computer and Information Sciences, DNA repair, Female, Genes, Genetic aspects, Genomes, Genomic instability, Genomics, Gynecology, Haploinsufficiency, Liquid chromatography, Medicine, Medicine and Health Sciences, Membrane lipids, Metabolome, Metabolomics, Mice, Microtubule-Associated Proteins - genetics, Molecular biology, Mutation, Neurobiology, Neurodegeneration, Neurosciences, Obstetrics, Ovarian cancer, Ovarian Neoplasms - genetics, Ovarian Neoplasms - metabolism, Ovarian Neoplasms - pathology, Ovarian tumors, Pediatrics, Phagocytosis, Phospholipids, Plant lipids, Quality control, Research and Analysis Methods, Scientific equipment industry, Spectroscopy, Sphingolipids, Tumor antigens, Tumor suppressor genes, Tumorigenesis, Tumors