RESUMO
Progresses in multimodal treatments have significantly improved the outcomes for childhood cancer. Nonetheless, for about one-third of patients with Ewing sarcoma, rhabdomyosarcoma, or osteosarcoma steady remission has remained intangible. Thus, new biomarkers to improve early diagnosis and the development of precision-targeted medicine remain imperative. Over the last decade, remarkable progress has been made in the basic understanding of miRNAs function and in interpreting the contribution of their dysregulation to cancer development and progression. On this basis, this review focuses on what has been learned about the pivotal roles of miRNAs in the regulation of key genes implicated in childhood sarcomas.
Assuntos
Neoplasias Ósseas/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , Rabdomiossarcoma/metabolismo , Sarcoma de Ewing/metabolismo , Neoplasias Ósseas/genética , Criança , Regulação para Baixo , Humanos , Osteossarcoma/genética , Rabdomiossarcoma/genética , Sarcoma de Ewing/genética , Regulação para CimaRESUMO
miRNAs have been identified as key regulators of almost all cellular processes, therefore, their dysregulation is involved with several diseases, including cancer. miRNAs specifically related to the metastastic cascade are called metastamiRs and can be involved with different steps of this process, including loss of adhesion. Osteosarcoma (OS) is the most common primary malignant pediatric bone tumor that often presents metastatic disease at diagnosis; therefore, a deeper study of adhesion-associated miRNAs could shed light on its pathophysiology. Online databases were used to select four miRNAs (miR-139; miR-181b; miR-584; miR-708) predicted or validated to target proteins related to adherent junctions and focal adhesion pathways, and their expression levels and possible associations with clinical features evaluated in primary OS samples. Our results showed downregulation of miR-139-5p and miR-708-5p in OS samples compared to non-neoplastic controls. Moreover, lower expression of miR-708-5p was associated with poor overall survival and higher expression of miR-181b-5p related to worst chemotherapy response (low HUVOS level). Based on these results, we selected miR-139-5p and miR-708-5p for further functional testing. Inducing the expression of miR-139-5p diminished the clonogenic capacity of the HOS cell line, while upregulation of miR-708-5p was related to a lower cellular adhesion. In summary, this work identified new signatures of microRNA dysregulation that may serve as useful prognostic markers in this aggressive pediatric bone tumor.
Assuntos
Junções Aderentes/genética , Biomarcadores Tumorais/genética , Neoplasias Ósseas/secundário , Adesões Focais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Osteossarcoma/patologia , Adolescente , Adulto , Neoplasias Ósseas/genética , Neoplasias Ósseas/cirurgia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Osteossarcoma/genética , Osteossarcoma/cirurgia , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
We report two similarly affected cousins (children of monozygotic twin sisters) with phenotypic features consistent with 9p deletion syndrome, including dysmorphic craniofacial features (trigonocephaly, midface hypoplasia, upward-slanting palpebral fissures and long philtrum), intellectual disability and disorders of sex development. Initial cytogenetic examination showed normal karyotypes in the probands and their respective parents, though multiplex ligation probe amplification revealed a 1q terminal duplication and a 9p terminal deletion in both affected children. Further analysis by fluorescence in situ hybridization, identified a familial balanced cryptic translocation t(1;9)(q44;p23) in the mothers, showing the importance of the association of molecular cytogenetic techniques in clinical genetics, given the implications for the care of patients and for genetic counseling.
Assuntos
Hibridização in Situ Fluorescente/métodos , Translocação Genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 9/genética , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Polo-like kinase 1 (PLK1) is a conserved kinase that mediates various mitotic events. Compelling data have repeatedly demonstrated its upregulation in different neoplasia, being frequently associated with poor prognosis. However, in childhood acute lymphoblastic leukemia (ALL), no studies have yet been conducted. PROCEDURE: PLK1 expression and association with biological features were evaluated in 65 consecutively diagnosed childhood ALL samples by quantitative real-time PCR. Moreover, the effects of a specific PLK1 inhibitor, BI 2536, was tested against a panel of nine ALL cell lines at nanomolar concentrations (10, 50, 100 nM). RESULTS: The mRNA expression of PLK1 showed great variability in pediatric ALL, but no difference was evidenced compared to normal bone marrow. Additionally, no association was found between PLK1 mRNA expression with any clinical or biological features. Alternatively, high mRNA expression of PLK1 was present in ALL cell lines. In vitro treatment with BI 2536 strongly diminished growth, while presenting significant reduction in colony formation capacity and increased apoptosis rates. Moreover, strong G2/M arrest was detected suggesting important impaired proliferation after treatment. CONCLUSIONS: PLK1 mRNA expression level is not associated with prognosis in childhood ALL; however, considering the great variability observed in the sample and the in vitro experiments presented herein, BI 2536 treatment might serve as a promising therapeutic to enhance the efficacy of conventional treatment modalities in some childhood ALL cases.
Assuntos
Proteínas de Ciclo Celular , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Pteridinas/farmacologia , Adolescente , Medula Óssea/metabolismo , Medula Óssea/patologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/biossíntese , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Lactente , Células Jurkat , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/biossíntese , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Estudos Retrospectivos , Taxa de Sobrevida , Quinase 1 Polo-LikeRESUMO
Despite advances in neurosurgery and aggressive treatment with temozolomide (TMZ) and radiation, the overall survival of patients with glioblastoma (GBM) remains poor. Vast evidence has indicated that the nuclear factor NF- κ B is constitutively activated in cancer cells, playing key roles in growth and survival. Recently, Dehydroxymethylepoxyquinomicin (DHMEQ) has shown to be a selective NF- κ B inhibitor with antiproliferative properties in GBM. In the present study, the ability of DHMEQ to surmount tumor's invasive nature and therapy resistance were further explored. Corroborating results showed that DHMEQ impaired cell growth in dose- and time-dependent manners with G2/M arrest when compared with control. Clonogenicity was also significantly diminished with increased apoptosis, though necrotic cell death was also observed at comparable levels. Notably, migration and invasion were inhibited accordingly with lowered expression of invasion-related genes. Moreover, concurrent combination with TMZ synergistically inhibited cell growth in all cell lines, as determined by proliferation and caspase-3 activation assays, though in those that express O(6)-methylguanine-DNA methyltransferase, the synergistic effects were schedule dependent. Pretreatment with DHMEQ equally sensitized cells to ionizing radiation. Taken together, our results strengthen the potential usefulness of DHMEQ in future therapeutic strategies for tumors that do not respond to conventional approaches.
RESUMO
Osteochondroma is a cartilage capped benign tumor developing mainly at the juxta-epiphyseal region of long bones. The rate of malignant transformation, mainly into chondrosarcoma, is estimated to be less than 1-3%. Transformation into osteosarcoma is very rare and has been reported only thirteen times. There is little information on treatment and outcome. We report the case of a secondary osteosarcoma arising in the left tibia of a 23-year-old male, 10 years after the initial diagnosis of osteochondroma and after two partial resections. Malignant transformation occurred at the stalk and not at the cartilage cap, as would normally be expected. Chromosome banding analysis revealed the karyotype: 46,XY, t(3;13)(q21;q34) [2]/46,XY [18]. Records from additional cases will help determine the parameters that define these rare secondary bone lesions.
Assuntos
Osteocondroma/patologia , Osteossarcoma/secundário , Tíbia/patologia , Adulto , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Bandeamento Cromossômico/métodos , Humanos , Cariótipo , Masculino , Osteocondroma/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Osteossarcoma/cirurgia , Adulto JovemRESUMO
Genetic instability is frequent in human cancer. Unscheduled tetraploidization can trigger cell transformation and tumorigenesis. We made a cytogenetic analysis by Giemsa-trypsin banding of a stage I, biphasic Wilms tumor diagnosed in a 10-month-old male. An evident karyotypic heterogeneity was found. Four different subclones of tumor cells were observed, with DNA content varying from diploid to near-tetraploid complements. The genetic events involved in the acquisition of aneuploidy in Wilms tumor remain unclear. We hypothesize that initial tetraploidization caused aberrant cell division, leading to abnormal chromosomal segregation, cell transformation and tumorigenesis.
Assuntos
Aneuploidia , Tumor de Wilms/genética , Humanos , Lactente , Cariotipagem , MasculinoRESUMO
Epithelioid sarcoma is a rare, aggressive soft tissue tumor of unknown histogenesis showing predominantly epithelioid cytomorphology. We conducted a conventional and molecular cytogenetic study of a 27-year-old male with epithelioid sarcoma with angiomatoid features. Cytogenetic analysis of epithelioid sarcoma metaphase spreads by GTG-banding revealed a diploid chromosome complement with structural and numerical aberrations. Comparative genomic hybridization analysis demonstrated the amplification of 3p24-pter, 4p15.2-p16 and 18q23, while chromosome losses involved 3p13-p14, 3q24-q26.1, 9q21, and 11q21. Fluorescence in situ hybridization assessment showed normal hybridization patterns for the C-MYC and CCND1 loci; CCND1 RNA overexpression was detected by real-time polymerase chain reaction analysis. Genetic evaluation of this rare condition may be useful in determining if epithelioid sarcoma is associated with a distinct genetic background.
Assuntos
Aberrações Cromossômicas , Sarcoma/genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Hibridização in Situ Fluorescente , Masculino , Reação em Cadeia da Polimerase , Sarcoma/tratamento farmacológicoRESUMO
Hematopoietic neoplasias are characterized by recurrent chromosomal aberrations that result in the formation of gene fusions and the subsequent expression of chimeric proteins with unique properties. However, in recent years, different lymphoma/leukemia-associated rearrangements, such as BCR/ABL, IGH/BCL2, ETV6/RUNX1 and MLL duplications, have been detected in healthy individuals. The presence of these rearrangements indicates that such translocations can be generated in normal hematopoietic cells without apparent oncogenic consequences. This article reviews and discusses the data available in the literature.