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1.
Cell Signal ; 88: 110167, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34628002

RESUMO

Artesunate (ART), a water-soluble derivative of artemisinin, has been reported to exert antineoplastic effects via diverse mechanisms in various types of cancer. Therefore, understanding the underlying mechanism of action of ART in distinct cancer types is indispensable to optimizing the therapeutic application of ART for different types of cancer. The present study aimed to investigate the cellular and molecular mechanisms responsible for the antineoplastic effects of ART in diffuse large B cell lymphoma (DLBCL) cells. Cell proliferation was measured using Cell Counting Kit-8 and colony formation assays. The levels of apoptosis and cell cycle distribution were investigated using flow cytometry. In addition, western blotting was used to analyze the expression levels of ART-induced apoptosis-, autophagy- and ferroptosis-related proteins. Monodansylcadaverine staining was performed to determine the levels of autophagy. Moreover, malondialdehyde and reactive oxygen species assays were used to determine the levels of ferroptosis. The results of the present study revealed that ART inhibited proliferation, and induced apoptosis, cell cycle arrest, autophagy and ferroptosis in DLBCL cells. Pharmacological inhibition of autophagy and ferroptosis alleviated the increased levels of apoptosis induced by ART. Notably, ART was found to exert its effects via inhibition of STAT3 activation. The genetic knockdown of STAT3 enhanced ART-induced autophagy and ferroptosis, and concomitantly upregulated the expression levels of apoptosis- and cell cycle-related proteins. In conclusion, the findings of the current study suggested that ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in DLBCL cells.

2.
BMC Cancer ; 21(1): 955, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433456

RESUMO

BACKGROUND: The improved prognosis of classic Hodgkin lymphoma (cHL) has been accompanied by elevated risks of non-cancer-specific death (non-CSD). The aim of this study was to verify the occurrence of non-CSD and its effect on rates of overall survival among adult patients with cHL. METHODS: To ensure sufficient follow-up time, we analyzed retrospective data from patients aged ≥20 years with cHL that was diagnosed between 1983 and 2005 in the Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was applied to analyze the non-CSD occurrence in relation to all factors. Using Fine-Gray's method, we calculated the cumulative incidences of CSD and non-CSD. Stacked cumulative incidence plots and ratio of non-CSD to all causes of death were applied to evaluate the effect of non-CSD on rates of overall survival. Finally, we analyzed long-term mortality through Cox proportional hazard regression analysis and competing risk regression analysis to emphasize a more appropriate model of survival for patients with cHL. RESULTS: Among the 18,518 patients included, there were 3768 cases of CSD (20.3%) and 3217 of non-CSD (17.4%). Older age, earlier period, male sex, unmarried status, mixed cellularity (MC) and lymphocyte-depletion (LD) histological subtype, and patients received radiotherapy (RT) only were associated with more non-CSD according to binary logistic analysis. The cumulative incidence of non-CSD exceeded CSD after approximately 280 months follow-up. The most common causes of non-CSDs were cardiovascular disease, subsequent primary neoplasms, infectious diseases, accidents, and suicide. In a Cox proportional hazards model, patients who were black, unmarried, at an advanced stage or underwent chemotherapy (CT) alone were at greater risk of mortality than were white patients, who were married, at an early stage, and underwent combined modality; these populations were also found to be at greater risk for CSD in a competing risk model, but the risk of non-CSD did not differ significantly according to race and marital status, patients with early-stage disease and who underwent RT only were found to be at higher risk of non-CSD instead. CONCLUSIONS: Lymphoma was the cause of death in most patients who died, but non-CSD was not unusual. Patients with cHL should be monitored closely for signs of cardiovascular disease and malignant tumors. Rates of overall survival of patients were diminished by non-CSD, and a competing risk model was more suitable for establishing the prognosis than was the Cox proportional hazards model.


Assuntos
Causas de Morte/tendências , Doença de Hodgkin/mortalidade , Programa de SEER/estatística & dados numéricos , Adulto , Terapia Combinada , Feminino , Seguimentos , Doença de Hodgkin/patologia , Doença de Hodgkin/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
3.
Am J Blood Res ; 11(1): 100-110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796397

RESUMO

INTRODUCTION: The inflammatory and immune cells have an important impact on Hodgkin lymphoma (HL). The derived neutrophil-lymphocyte ratio (dNLR) has been confirmed to have a similar prognostic value as the neutrophil-lymphocyte ratio (NLR) in many kinds of tumors, but it has not been explored as a prognostic marker for Hodgkin lymphoma patients. OBJECTIVE: The aim of the study is to evaluate the prognostic value of dNLR and NLR in HL. METHODS: This retrospective study included 213 newly diagnosed HL patients from 2008 to 2019. Then, the prognostic significance of dNLR and NLR in these patients was evaluated. Meanwhile, subgroup analyses based on the Ann Arbor stage and histotype were also carried out. Finally, propensity score matching was used to reduce selection bias. RESULTS: Patients with dNLR ≥ 2.1 showed shorter overall survival (OS) (P = 0.006). Also, patients with NLR ≥ 3.0 showed worse OS (P = 0.005) and progression-free survival (PFS) (P = 0.031). These results were also found in patients with early-stage and mixed cellularity subtype HL. Besides, high dNLR represented an independent prognostic marker for OS and high NLR remained an independent prognostic factor for OS and PFS on multivariable analysis. CONCLUSION: Elevated dNLR and NLR were related to worse survival in HL patients. For the first time, the dNLR has shown the potential to be a new prognostic factor for patients with HL.

4.
Cell Signal ; 72: 109643, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32320859

RESUMO

Transient Receptor Potential Melastatin Subfamily Member 4 (TRPM4) has been demonstrated to be aberrantly expressed in several cancers but seldom reported in acute leukemia. Based on database mining and validated experiments, our present data show that TRPM4 is selectively overexpressed in AML patients and cell lines with the MLL gene rearrangement. We analyzed the correlation between TRPM4 expression and clinical parameters in a validated cohort of AML patients. Increased TRPM4 expression was associated with significant leukocytosis (p = .028), M4/M5 subtype (p = .000), FLT3-ITD mutation (p = .034), MLL status (p = .007) and a higher risk stratification (p = .001). Knockdown of TRPM4 mediated by siRNA impaired proliferation and arrested the cell cycle at the G0/G1 phase in MLL-rearranged leukemia cells. We suggested that TRPM4 may be involved in the pathogenesis of MLL-rearranged leukemia through regulating the AKT/GLI1/Cyclin D1 pathway. The transcription factor HOXA9 was found to be responsible for upregulation of TRPM4 expression by binding to its promoter. In conclusion, TRPM4 is overexpressed in MLL-rearranged AML and blockade of TRPM4 may be an alternative therapeutic approach in AML patients with high TRPM4 expression.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Ciclina D1/metabolismo , Rearranjo Gênico/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Canais de Cátion TRPM/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Adulto , Estudos de Casos e Controles , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/metabolismo , Regiões Promotoras Genéticas/genética , Transdução de Sinais , Canais de Cátion TRPM/metabolismo , Transcrição Genética , Regulação para Cima/genética
5.
Oncol Lett ; 14(3): 3846-3852, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28927156

RESUMO

Glioblastoma multiforme is the most common and aggressive form of primary malignant brain tumor. Previous evidence demonstrates that ß-adrenergic receptors (ß-ARs) are closely associated with the occurrence and development of brain tumors. However, the functional role of ß-ARs in human glioblastoma and the underlying mechanisms are not fully understood. In the present study, by using the MTT assay, western blotting, and the reverse transcription polymerase chain reaction, it was revealed that isoproterenol (ISO), an agonist of ß-ARs, promoted the proliferation of U251 cells but not U87-MG cells, and that this effect was blocked by the ß-ARs antagonist propranolol. It was also demonstrated that ISO transiently induced extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation, and that blocking the mitogen-activated protein kinase pathway by U0126 inhibited ERK1/2 phosphorylation and suppressed U251 cell proliferation. In addition, ß-ARs activation increased the expression of matrix metalloproteinase (MMP) family members MMP-2 and MMP-9 mRNA through ERK1/2 activation. In conclusion, these data suggest that ß-ARs induce ERK1/2 phosphorylation, which may in turn increase MMPs expression to promote U251 cell proliferation. These results provide additional insight into the specific roles of ß-ARs in glioblastoma.

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