RESUMO
Genomic abnormalities are strongly associated with cancer and infertility. In this study, we develop a simple and efficient method - multiple genetic abnormality sequencing (MGA-Seq) - to simultaneously detect structural variation, copy number variation, single-nucleotide polymorphism, homogeneously staining regions, and extrachromosomal DNA (ecDNA) from a single tube. MGA-Seq directly sequences proximity-ligated genomic fragments, yielding a dataset with concurrent genome three-dimensional and whole-genome sequencing information, enabling approximate localization of genomic structural variations and facilitating breakpoint identification. Additionally, by utilizing MGA-Seq, we map focal amplification and oncogene coamplification, thus facilitating the exploration of ecDNA's transcriptional regulatory function.
Assuntos
Variações do Número de Cópias de DNA , Oncogenes , Genômica/métodos , Regulação da Expressão Gênica , DNARESUMO
The mechanism of dihydroartemisinin (DHA) inhibiting the migration and invasion of glioma in an ROS-DSB-dependent manner has been revealed. Extrachromosomal DNAs (ecDNAs) which are generated by DNA damage have great potential in glioma treatment. However, the role of ecDNAs in DHA's pharmacological mechanisms in glioma is still unknown. In this study, DHA was found to inhibit proliferative activity, increase ROS levels and promote apoptosis in U87 and U251 cells. Migration and invasion have also been suppressed. ecDNA expression profiles were found in gliomas. EcDNA-BASP1 was found, by means of bioinformatics analysis, to be present in GBM tissues and positively correlated with patient prognosis. Proliferation, migration and invasion were upregulated after knockdown of ecDNA-BASP1. The expression of vimentin and N-cadherin also had the same tendency. Finally, we found that the ecDNA-BASP1 content in nude mouse transplant tumors was significantly increased after DHA treatment, which might exert a better suppressive effect on glioma. The upregulation of tumor suppressor ecDNA-BASP1 played an important role in the suppression of glioma progression induced by DHA. EcDNA-BASP1 may inhibit glioma migration and invasion through repressing epithelial-mesenchymal transition (EMT).
Assuntos
Neoplasias Encefálicas , DNA de Forma B , Glioma , Animais , Camundongos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , HumanosRESUMO
Extrachromosomal DNA (ecDNA) is a cancer-specific circular DNA molecule that is derived from chromosomes. In contrast with linear chromosomes, ecDNA exhibits a unique structure that can be representative of high chromosome accessibility, contributing to hyperactivated proto-oncogenes and malignant behaviours. Meanwhile, nonchromosomal inheritance and recurrent mutations of ecDNA fuel tumour heterogeneity and evolution. Recent studies have demonstrated that ecDNA drives tumorigenesis and progression and is related to poor clinical outcomes and drug resistance across widespread cancers. Although ecDNA was first observed in 1965, with technological advancements, its critical functions in tumorigenesis are currently coming forth. In this review, we summarize the current understanding of the origin, biogenesis process, discovery history, molecular mechanisms, and physiological functions of ecDNAs in cancer. Additionally, we highlight the effective research methods to study ecDNA and offer novel insights for ecDNA-directed therapies.
Assuntos
Cromossomos , Neoplasias , Carcinogênese/genética , DNA/genética , DNA Circular/genética , Humanos , Neoplasias/genética , Neoplasias/patologia , Neoplasias/terapiaRESUMO
More and more extrachromosomal DNA (ecDNA) was found in human tumor cells in recent years, which has a high copy number in tumors and changes the expression of oncogenes, thus different from normal chromosomal DNA. These circular structures were identified to originate from chromosomes, and play critical roles in rapid carcinogenesis, tumor evolution and multidrug resistance. Therefore, this review mostly focuses on the biogenesis and regulation of extrachromosomal oncogene in ecDNA as well as its function and mechanism in tumors, which are of great significance for our comprehensive understanding of the role of ecDNA in tumor carcinogenic mechanism and are expected to provide ecDNA with the potential to be a new molecular target for the diagnosis and treatment of tumors.