The aim of this study was to evaluate the expression of USP7, USP15, UBE2O, and UBE2T genes in Myelodysplastic neoplasm (MDS) to identify possible targets of ubiquitination and deubiquitination in MDS pathobiology. To achieve this, eight datasets from the Gene Expression Omnibus (GEO) database were integrated, and the expression relationship of these genes was analyzed in 1092 MDS patients and healthy controls. Our results showed that UBE2O, UBE2T, and USP7 were upregulated in MDS patients compared with healthy individuals, but only in mononucleated cells collected from bone marrow samples (p < 0.001). In contrast, only the USP15 gene showed a downregulated expression compared with healthy individuals (p = 0.03). Additionally, the upregulation of UBE2T expression was identified in MDS patients with chromosomal abnormalities compared with patients with normal karyotypes (p = 0.0321), and the downregulation of UBE2T expression was associated with MDS hypoplastic patients (p = 0.033). Finally, the USP7 and USP15 genes were strongly correlated with MDS (r = 0.82; r2 = 0.67; p < 0.0001). These findings suggest that the differential expression of the USP15-USP7 axis and UBE2T may play an important role in controlling genomic instability and the chromosomal abnormalities that are a striking characteristic of MDS.
The sirtuins (SIRT) gene family (SIRT1 to SIRT7) contains the targets implicated in cellular and organismal aging. The role of SIRTs expression in the pathogenesis and overall survival of patients diagnosed with solid tumors has been widely discussed. However, studies that seek to explain the role of these pathways in the hematopoietic aging process and the consequences of their instability in the pathogenesis of different onco-hematological diseases are still scarce. Therefore, we performed a systematic review (registered in PROSPERO database #CRD42022310079) and in silico analysis (based on GEPIA database) to discuss the role of SIRTs in the advancement of pathogenesis and/or prognosis for different hematological cancer types. In summary, given recent available scientific evidence and in silico gene expression analysis that supports the role of SIRTs in pathobiology of hematological malignances, such as leukemias, lymphomas and myeloma, it is clear the need for further high-quality research and clinical trials that expands the SIRT inhibition knowledge and its effect on controlling clonal progression caused by genomic instability characteristics of these diseases. Finally, SIRTs represent potential molecular targets in the control of the effects caused by aging on the failures of the hematopoietic system that can lead to the involvement of hematological neoplasms.
Introdução: A relação entre a senescência e o câncer é alvo de estudos, tanto em contexto carcinogênico quanto na supressão tumoral. Considerados importantes marcadores de envelhecimento, as sirtuinas podem auxiliar na medicina preventiva do câncer. Entretanto, estudos com esses marcadores em Síndrome Mielodisplásica ainda são escassos. Objetivo: Investigar o papel das sirtuinas (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 e SIRT7) na patogênese e na evolução prognóstica da Síndrome Mielodisplásica em um estudo do tipo caso-controle retro-prospectivo. Metodologia: Foram selecionados 106 pacientes diagnosticados para SMD e 11 indivíduos saudáveis pareados por sexo e idade cujo as amostras de aspirado de medula óssea serão coletadas e armazenadas em freezer -80°. Análises de citogenética por banda G foram realizadas para todos os pacientes e as expressões das sirtuinas serão realizadas por RT-qPCR. Análises in sílico de predição de expressão gênica das sirtuinas foram realizadas pelo GEPIA (Gene Expression Profilling Interactive Analysis). Os achados citogenéticos e moleculares serão correlacionados com dados clínico-epidemiológicos e laboratoriais coletados via banco RedCap. Resultados Preliminares: Em análise de dados clínico-epidemiológicos, verificou-se que os pacientes são, predominantemente, do sexo feminino (55,26%) com idade média de 69 anos (70,30%). Os pacientes apresentaram, prioritariamente, cariótipo normal (57,89%) enquanto 25% apresentaram alterações citogenéticas, principalmente relacionadas à del(5q) e +7. Em análise de predição in sílico, foi identificado que, para LMA, SIRT3, SIRT4, SIRT5 e SIRT7 estavam downregulated, enquanto que a expressão de SIRT1 e SIRT2 estavam upregulated quando comparada aos tecidos normais (p<0.05). Conclusão: Este é o primeiro estudo que irá relacionar o papel das sirtuinas na patobiologia da SMD. Atualmente, estamos em fase final de recrutamento dos indivíduos de grupo controle e início das análises de expressão gênica. Assim, a partir da análise in sílico, espera-se que a expressão das sirtuinas possa representar possíveis novos marcadores de diagnóstico e prognóstico para SMD.
Myelodysplastic Syndromes (MDS) are a group of heterogeneous hematologic disorders characterized by bone marrow involvement. Iron overload is the result of multiple transfusions and high levels of apoptosis. Based on a literature review, ferritin was identified as an important marker of iron accumulation in organs such as liver, heart and pancreas in patients with MDS. Some studies also demonstrated that iron overload caused cell cycle arrest causing apoptosis and progression to leukemia, high levels of reactive oxygen species and low levels of HIF-1a, causing apoptosis, being related to the presence of cytopenia in MDS.
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