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1.
Hepatology ; 68(1): 89-102, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29152775

RESUMO

Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70%-80% of patients. However, some important challenges remain in diagnosing high-risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of HB tumors have been described, C1 and C2, with C2 being the subgroup with the poorest prognosis, a more advanced tumor stage, and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed, but it has not been transferred into clinical routine. To address these issues, we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A, and C2B, identifiable by a concise four-gene signature: hydroxysteroid 17-beta dehydrogenase 6, integrin alpha 6, topoisomerase 2-alpha, and vimentin, with topoisomerase 2-alpha being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by quantitative RT-PCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in the Fanconi anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, a Food and Drug Administration-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway-associated double-strand DNA repair, and significantly impedes HB growth in vivo. CONCLUSION: The highly proliferating C2A subtype is characterized by topoisomerase 2-alpha gene up-regulation and FA pathway activation, and the HB therapeutic arsenal could include bortezomib for the treatment of patients with the most aggressive tumors. (Hepatology 2018;68:89-102).


Assuntos
DNA Topoisomerases Tipo II/metabolismo , Hepatoblastoma/classificação , Hepatoblastoma/genética , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores/metabolismo , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Reparo do DNA/efeitos dos fármacos , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Perfilação da Expressão Gênica , Células Hep G2 , Hepatoblastoma/tratamento farmacológico , Hepatoblastoma/enzimologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Análise de Sequência de RNA
2.
Oncogene ; 38(33): 6083-6094, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31270395

RESUMO

Oncogenesis is considered to result from chromosomal instability, in addition to oncogene and tumor-suppressor alterations. Intermediate to aneuploidy and chromosomal instability, genome doubling is a frequent event in tumor development but the mechanisms driving tetraploidization and its impact remain unexplored. Cell fusion, one of the pathways to tetraploidy, is a physiological process involved in mesenchymal cell differentiation. Besides simple genome doubling, cell fusion results in the merging of two different genomes that can be destabilized upon proliferation. By testing whether cell fusion is involved in mesenchymal oncogenesis, we provide evidence that it induces genomic instability and mediates tumor initiation. After a latency period, the tumor emerges with the cells most suited for its development. Furthermore, hybrid tumor genomes were stabilized after this selection process and were very close to those of human pleomorphic mesenchymal tumors. Thus genome restructuring triggered by cell fusion may account for the chromosomal instability involved in oncogenesis.


Assuntos
Aneuploidia , Transformação Celular Neoplásica/genética , Instabilidade Cromossômica/fisiologia , Células Híbridas/citologia , Células Híbridas/metabolismo , Neoplasias/genética , Animais , Fusão Celular , Células Cultivadas , Instabilidade Genômica , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Neoplasias/patologia , Tetraploidia
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