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1.
PLoS Comput Biol ; 15(11): e1007493, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31738747

RESUMO

A tumour grows when the total division (birth) rate of its cells exceeds their total mortality (death) rate. The capability for uncontrolled growth within the host tissue is acquired via the accumulation of driver mutations which enable the tumour to progress through various hallmarks of cancer. We present a mathematical model of the penultimate stage in such a progression. We assume the tumour has reached the limit of its present growth potential due to cell competition that either results in total birth rate reduction or death rate increase. The tumour can then progress to the final stage by either seeding a metastasis or acquiring a driver mutation. We influence the ensuing evolutionary dynamics by cytotoxic (increasing death rate) or cytostatic (decreasing birth rate) therapy while keeping the effect of the therapy on net growth reduction constant. Comparing the treatments head to head we derive conditions for choosing optimal therapy. We quantify how the choice and the related gain of optimal therapy depends on driver mutation, metastasis, intrinsic cell birth and death rates, and the details of cell competition. We show that detailed understanding of the cell population dynamics could be exploited in choosing the right mode of treatment with substantial therapy gains.


Assuntos
Citostáticos/farmacologia , Citotoxinas/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Evolução Biológica , Progressão da Doença , Humanos , Modelos Biológicos , Modelos Teóricos , Mutação , Processos Neoplásicos
2.
PLoS Comput Biol ; 15(8): e1007246, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31374072

RESUMO

Successful prediction of the likely paths of tumor progression is valuable for diagnostic, prognostic, and treatment purposes. Cancer progression models (CPMs) use cross-sectional samples to identify restrictions in the order of accumulation of driver mutations and thus CPMs encode the paths of tumor progression. Here we analyze the performance of four CPMs to examine whether they can be used to predict the true distribution of paths of tumor progression and to estimate evolutionary unpredictability. Employing simulations we show that if fitness landscapes are single peaked (have a single fitness maximum) there is good agreement between true and predicted distributions of paths of tumor progression when sample sizes are large, but performance is poor with the currently common much smaller sample sizes. Under multi-peaked fitness landscapes (i.e., those with multiple fitness maxima), performance is poor and improves only slightly with sample size. In all cases, detection regime (when tumors are sampled) is a key determinant of performance. Estimates of evolutionary unpredictability from the best performing CPM, among the four examined, tend to overestimate the true unpredictability and the bias is affected by detection regime; CPMs could be useful for estimating upper bounds to the true evolutionary unpredictability. Analysis of twenty-two cancer data sets shows low evolutionary unpredictability for several of the data sets. But most of the predictions of paths of tumor progression are very unreliable, and unreliability increases with the number of features analyzed. Our results indicate that CPMs could be valuable tools for predicting cancer progression but that, currently, obtaining useful predictions of paths of tumor progression from CPMs is dubious, and emphasize the need for methodological work that can account for the probably multi-peaked fitness landscapes in cancer.


Assuntos
Modelos Biológicos , Neoplasias/genética , Neoplasias/patologia , Teorema de Bayes , Biologia Computacional , Simulação por Computador , Estudos Transversais , Bases de Dados Factuais , Progressão da Doença , Evolução Molecular , Aptidão Genética , Genótipo , Humanos , Modelos Genéticos , Mutação , Processos Neoplásicos , Prognóstico
4.
Artigo em Chinês | MEDLINE | ID: mdl-31315361

RESUMO

Objective: To compare the carcinogenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells and to identify the mechanism underlying the action of miRNAs. Methods: Solid tumor-derived laryngeal carcinoma stem cells and Hep-2-derived laryngeal carcinoma stem cells were cultured, and CD133(+)CD44(+) laryngeal cancer stem cells were sorted by flow cytometry. Boden chamber invasion assay, cell migration assay and tumor formation assay were then performed to compare the invasion, migration and tumorigenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells. And then, miRNAs isolated from two laryngeal cancer stem cells were detected and analysed with miRNA chip. Results: (1)In Boyden chamber invasion assay, the cell invasion rate of CD133(+)CD44(+) laryngeal cancer stem cells was obviously higher (80.2%±2.3% vs. 63.9%±3.2%, t=5.011, P=0.027); (2)CD133(+)CD44(+) laryngeal cancer stem cells also had higher mobility in cell migration assay (82.9%±1.1% vs. 70.9%±0.6%, t=4.514, P=0.031); (3)In tumor formation assay, the tumor formation rate of CD133(+)CD44(+) laryngeal cancer stem cells was also higher (80% vs. 50%). What's more, we identified 15 miRNAs that were significantly upregulated in CD133(+)CD44(+) laryngeal cancer stem cells and 3 miRNAs that were significantly downregulated in CD133(+)CD44(+) laryngeal cancer stem cells, compared with normal laryngeal cancer stem cells. Conclusions: CD133(+)CD44(+) laryngeal cancer stem cells have stronger invasion, migration and tumorigenic abilities compared with normal laryngeal cancer stem cells, and the difference of miRNAs' expression is one of the possible causes.


Assuntos
Neoplasias Laríngeas/fisiopatologia , MicroRNAs/biossíntese , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Antígeno AC133/biossíntese , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Humanos , Receptores de Hialuronatos/biossíntese , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Laringe/metabolismo , Laringe/patologia , Laringe/fisiopatologia , Invasividade Neoplásica/fisiopatologia , Processos Neoplásicos
6.
Rev. Eugenio Espejo ; 13(1): 53-61, Ene-Jul. 2019.
Artigo em Espanhol | LILACS | ID: biblio-1006782

RESUMO

Caso clínico: paciente masculino de 81 años de edad, con cuadro de 24 horas de evolución secundario a caída, caracterizado por somnolencia, desorientación en persona, tiempo y espacio, incontinencia urinaria y dificultad para la deambulación, motivo por el cual se le efectúa una tomografía simple de cráneo encontrándose hematomas subdurales bilaterales, presenta episodios de sangrado recurrente y leucocitosis sostenida , en frotis de sangre periférica se observó 28% de blastos por lo que se realiza una biopsia de medula ósea descubriéndose un cariotipo medular compatible con leucemia mieloide aguda, debido a sus características clínicas y a su mala evolución fue catalogado como paciente paliativo. Conclusiones: la leucemia mieloide aguda es una patología hematológica cuya evolución al no ser detectada genera un alto grado de mortalidad, sobre todo en el adulto mayor comórbido.


It was presented a clinical case of a male patient of 81 years of age, with a 24-hour of secondary evolution to a fall. It was characterized by drowsiness, disorientation in person, time and space, urinary incontinence and difficulty in walking, that was why a simple skull tomography was performed, in which bilateral subdural hematomas were found. The patient presented episodes of recurrent bleeding and sustained leukocytosis. Peripheral blood smear showed 28% of blasts, so a bone marrow biopsy was performed, revealing a medullary karyotype compatible with acute myeloid leukemia. The patient was classified as palliative due to its clinical characteristics and evolution. The hematological pathology above was potentially fatal. If this one was not detected early, it would generate an accelerated unfavorable evolution, especially in the elderly comorbid, as occurred in the case presented.


Assuntos
Humanos , Masculino , Idoso de 80 Anos ou mais , Neoplasias Hematológicas , Doenças Hematológicas , Doenças Sanguíneas e Linfáticas , Síndromes Paraneoplásicas , Neoplasias , Processos Neoplásicos
7.
Pathol Res Pract ; 215(8): 152454, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146977

RESUMO

Alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC) is regarded as a rare but highly malignant gastric adenocarcinoma subtype and its clinic pathological presentation mimics hepatocellular carcinoma. However, the underlying mechanism of this disease remains elusive. The level of ANGPTL6 in AFPGC cell lines is much higher than that of common types of gastric cancer cells. A high level of ANGPTL6 confers a poor prognosis and is correlated with the expression of CD34 (an endothelial cell marker). ANGPTL6 promotes endothelial cell migration and tube formation, Moreover, ANGPTL6 knockdown inhibits cancer cell apoptosis and invasiveness. Mechanistically, ANGPTL6 activates the ERK1/2 and AKT pathways. Treatment of ERK1/2 or AKT inhibitor can attenuated cell migration and tube formation. ANGPTL6 loss results in tumor growth in vivo. Our study revealed that ANGPTL6 is an important driver gene of angiogenesis in AFPGC development. These findings provide not only an effective biomarker for diagnosis but also an attractive therapeutic target for use in AFPGC patients.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Neovascularização Patológica/patologia , Neoplasias Gástricas/patologia , alfa-Fetoproteínas/metabolismo , Proteínas Semelhantes a Angiopoietina/genética , Progressão da Doença , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Processos Neoplásicos , Neovascularização Patológica/genética , Estômago/patologia , Neoplasias Gástricas/genética , alfa-Fetoproteínas/genética
9.
Cells ; 8(5)2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083403

RESUMO

HIF-1 serves as an important regulator in cell response to hypoxia. Due to its key role in promoting tumor survival and progression under hypoxia, HIF-1 has become a promising target of cancer therapy. Thus far, several HIF-1 inhibitors have been identified, most of which are from synthesized chemical compounds. Here, we report that ALM (ActinoLactoMycin), a compound extracted from metabolites of Streptomyces flavoretus, exhibits inhibitory effect on HIF-1α. Mechanistically, we found that ALM inhibited the translation of HIF-1α protein by suppressing mTOR signaling activity. Treatment with ALM induced cell apoptosis and growth inhibition of cancer cells both in vitro and in vivo in a HIF-1 dependent manner. More interestingly, low dose of ALM treatment enhanced the anti-tumor effect of Everolimus, an inhibitor of mTOR, suggesting its potential use in combination therapy of tumors, especially solid tumor patients. Thus, we identified a novel HIF-1α inhibitor from the metabolites of Streptomyces flavoretus, which shows promising anti-cancer potential.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ácidos Graxos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lactonas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/uso terapêutico , Everolimo/farmacologia , Everolimo/uso terapêutico , Ácidos Graxos/uso terapêutico , Humanos , Lactonas/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Processos Neoplásicos , Células PC-3 , Transdução de Sinais/efeitos dos fármacos , Streptomyces/metabolismo , Serina-Treonina Quinases TOR/metabolismo
10.
Biochimie ; 166: 233-250, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31071357

RESUMO

Cystatins are endogenous and reversible inhibitors of cysteine peptidases that are important players in cancer progression. Besides their primary role as regulators of cysteine peptidase activity, cystatins are involved in cancer development and progression through proteolysis-independent mechanisms. Mechanistic studies of cystatin function revealed that they affect all stages of cancer progression including tumor growth, apoptosis, invasion, metastasis and angiogenesis. Recently, the involvement of cystatins in the antitumor immune responses was reported. In this review, we discuss molecular mechanisms and clinical aspects of cystatins in cancer. Altered expression of cystatins in cancer resulting in harmful excessive cysteine peptidase activity has been a subject of several studies in order to find correlations with clinical outcome and therapy response. However, involvement in anti-tumor immune response and signaling cascades leading to cancer progression designates cystatins as possible targets for development of new anti-tumor drugs.


Assuntos
Biomarcadores Tumorais/metabolismo , Cistatinas/metabolismo , Neoplasias/patologia , Animais , Apoptose , Biomarcadores Tumorais/química , Cistatinas/química , Desenho de Drogas , Humanos , Camundongos , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Processos Neoplásicos , Neovascularização Patológica/enzimologia
11.
Nat Rev Cancer ; 19(6): 301, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31065050
12.
FEBS Open Bio ; 9(4): 605-617, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30984536

RESUMO

We previously reported that the expression of G protein-coupled receptor kinase 6 (GRK6) is significantly downregulated in lung adenocarcinoma (LADC) tissues, and low expression levels of GRK6 are correlated with poor survival prognosis. However, the specific regulatory mechanisms and functions of GRK6 in LADC remain unknown. Here, we report that GRK6 mRNA expression levels are downregulated in LADC tissues compared to those in matched adjacent non-tumor tissues (P < 0.001). The promoter of the GRK6 gene was found to be hypermethylated in LADC tissues, and its methylation was correlated with both GRK6 expression and pathology grade. GRK6 promoter hypermethylation may predict shorter overall survival. Treatment with 5-aza-2'-deoxycytidine significantly enhanced GRK6 gene expression. Four binding sites of CCAAT/enhancer-binding protein-α (C/EBPα) in the CpG island of the GRK6 gene promoter were predicted in silico, of which three sites were further confirmed by ChIP. Decreased binding of C/EBPα to binding sites 1, 3 and 4 of the GRK6 gene promoter was observed in LADC tissues. Inhibition of C/EBPα significantly inhibited GRK6 expression, while overexpression of C/EBPα significantly promoted GRK6 expression. In addition, overexpression of GRK6 significantly suppressed, while GRK6 knockdown promoted cell migration and invasion. Overexpression of GRK6 enhanced E-cadherin expression and suppressed vimentin expression, and silencing of GRK6 had the opposite effects. Furthermore, ectopic expression of GRK6 significantly decreased matrix metalloproteinase (MMP) 2 and MMP7 protein expression levels. Our findings suggest that hypermethylation of the GRK6 gene promoter suppressed binding of C/EBPα, thereby contributing to the promotion of cell migration and invasion. The methylation status of the GRK6 promoter might be suitable for use as an epigenetic biomarker, and the C/EBPα-GRK6 signaling pathway may be a potential target for LADC.


Assuntos
Adenocarcinoma de Pulmão/genética , Proteínas Estimuladoras de Ligação a CCAAT/genética , Quinases de Receptores Acoplados a Proteína G/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/genética , Regiões Promotoras Genéticas , Adenocarcinoma de Pulmão/fisiopatologia , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Movimento Celular , Metilação de DNA , Feminino , Quinases de Receptores Acoplados a Proteína G/química , Quinases de Receptores Acoplados a Proteína G/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Processos Neoplásicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
13.
Virchows Arch ; 474(6): 721-734, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30868297

RESUMO

Current histoprognostic parameters and prognostic scores used in paragangliomas and pheochromocytomas do not adequately predict the risk of metastastic progression and survival. Here, using a series of 147 cases of paraganglioma and pheochromocytoma, we designed and evaluated the potential of a new score, the COPPS (COmposite Pheochromocytoma/paraganglioma Prognostic Score), by taking into consideration three clinico-pathological features (including tumor size, necrosis, and vascular invasion), and the losses of PS100 and SDHB immunostain to predict the risk of metastasis. We compared also the performance of the COPPS with several presently used histoprognostic parameters in risk assessment of these tumors. A PASS score (Pheochromocytoma of the Adrenal gland Scaled Score) ≥ 6 was significantly associated with the occurrence of metastases (P < 0.0001) and shorter PFS (P = 0.013). In addition, both MCM6 and Ki-67 LI correlated with worse PFS (P = 0.004 and P < 0.0001, respectively), and MCM6, but not Ki-67, was significantly higher in metastatic group (P = 0.0004). Loss of PS100 staining correlated with the occurrence of metastasis (P < 0.0001) and shorter PFS (P < 0.0001). At a value of greater or equal to 3, the COPPS correlated with shorter PFS (P < 0.0001), and predicted reproducibly (weighted Kappa coefficient, 0.863) the occurrence of metastases with a sensitivity of 100.0% and specificity of 94.7%. It thus surpassed those found for either PASS, SDHB, MCM6, or Ki-67 alone. In conclusion, while validation is still necessary in independent confirmatory cohorts, COPPS could be of great potential for the risk assessment of metastasis and progression in paragangliomas and pheochromocytomas.


Assuntos
Metástase Neoplásica/diagnóstico , Paraganglioma/mortalidade , Feocromocitoma/mortalidade , Feocromocitoma/patologia , Adolescente , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Processos Neoplásicos , Prognóstico , Intervalo Livre de Progressão , Medição de Risco , Adulto Jovem
14.
Nat Rev Cancer ; 19(5): 248, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30923351
15.
J Craniofac Surg ; 30(4): 1231-1233, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30908440

RESUMO

In the present study, the authors assessed the differences in natural growth rates between skull base and non-skull base meningiomas by meta-analysis. Studies investigating meningioma growth rate were compiled from PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature database, and the China National Knowledge Infrastructure databases. A systematic review and meta-analysis of the collected literature were conducted using Stata 12.0 software. A total of 7 observational cohort studies, including 361 patients with untreated meningiomas, were included in the study. Meta-analysis showed that the weighted mean difference for absolute growth rate (years), relative growth rate (years), and doubling time (month) were 0.42 (95% confidence interval [CI]: 0.20-0.64, P <.0001), 1.08 (95%CI: 0.85-1.32, P <.0001), and -0.56 [95%CI: (-0.78)-(-0.33), P <.0001)] respectively. These findings indicate that the natural growth rate of skull base meningioma is less than that of non-skull base meningioma.


Assuntos
Neoplasias Encefálicas/patologia , Meningioma/patologia , Neoplasias da Base do Crânio/patologia , Proliferação de Células , Progressão da Doença , Humanos , Processos Neoplásicos
16.
Cancer Commun (Lond) ; 39(1): 3, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728082

RESUMO

BACKGROUND: In our previous study, we identified a candidate tumor suppressor gene, testin LIM domain protein (TES), in primary gastric cancer (GC). TES contains three LIM domains, which are specific interacting regions for the cell adhesion and cytoskeleton regulatory proteins. Mena is a known cytoskeleton regulator that regulates the assembly of actin filaments and modulates cell adhesion and motility by interacting with Lamellipodin (Lpd). Therefore, we hypothesized that TES plays a role as tumor suppressor in GC through interacting with Mena. This study aimed to investigate the tumor suppressive functions of TES in GC. METHODS: We explored the tumor suppressive effect of TES in GC by in vitro cell proliferation assay, colony formation assay, cell cycle analysis, Transwell assays, and in vivo tumorigenicity and metastasis assays. The interaction of TES and Mena was investigated through immunoprecipitation-based mass spectrometry. We also analyzed the expression of TES and Mena in 172 GC specimens using immunohistochemistry and investigated the clinicopathological and prognostic significance of TES and Mena in GC. RESULTS: TES suppressed GC cell proliferation and colony formation, induced cell cycle arrest, and inhibited tumorigenicity in vitro. Additionally, it inhibited GC cell migration and invasion in vitro and suppressed metastasis in vivo. TES interacted with Mena, and inhibited the interaction of Mena with Lpd. Transwell assays suggested that TES suppressed migration and invasion of GC cells in a Mena-dependent fashion. In GC patients with high Mena expression, the expression of TES was associated with tumor infiltration (P = 0.005), lymph node metastasis (P = 0.003), TNM stage (P = 0.003), and prognosis (P = 0.010). However, no significant association was observed in GC patients with low Mena expression. CONCLUSIONS: We believe that TES functions as a Mena-dependent tumor suppressor. TES represents a valuable prognostic marker and potential target for GC treatment.


Assuntos
Adenocarcinoma/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas com Domínio LIM/metabolismo , Proteínas dos Microfilamentos/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/patologia , Animais , Proteínas de Transporte/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas do Citoesqueleto/genética , Humanos , Proteínas com Domínio LIM/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Processos Neoplásicos , Neoplasias Gástricas/patologia , Proteínas Supressoras de Tumor/genética
17.
Biomed Res Int ; 2019: 1621854, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30766880

RESUMO

Background: Inflammation is the major risk factor for the progression of hepatocellular carcinoma (HCC), and the nuclear factor-κB (NF-κB) signaling plays the central role in the inflammation process. However, the activated mechanism of NF-κB signaling in HCC is unclear. Methods: The expression of PHF5A is examined by qPCR, western blotting, and immunohistochemistry (IHC) assay. The potential of PHF5A (PHD-finger domain protein 5a) for migration and invasion is examined by wound healing and Transwell assay. Luciferase reporter assay, western blotting, and qPCR were applied to explore the mechanism by which PHF5A is involved in progression of HCC. Results: PHF5A was significantly upregulated in HCC tissues and cells. Downregulation of PHF5A inhibits the migration and invasion of HCC cells. Further study demonstrated that PHF5A is implicated in HCC progression through NF-κB signaling. In addition, blocking the NF-κB signaling can weaken the stimulatory effect of PHF5A on migration and invasion of HCC cells. Conclusion: PHF5A expression is upregulated in HCC tissues, and depletion of PHF5A inhibits the migration and invasion of HCC cells. Further experiments demonstrated that PHF5A is implicated in NF-κB signaling and knockdown of PHF5A downregulates the activity of NF-κB pathway to inhibit the tumor progression. The above results provide the evidence that PHF5A plays an indispensable role in progressive effect of NF-κB pathway in HCC and may be a novel therapeutic target of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Transporte/genética , Movimento Celular/genética , Neoplasias Hepáticas/genética , NF-kappa B/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/biossíntese , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , NF-kappa B/genética , Invasividade Neoplásica , Processos Neoplásicos , Transdução de Sinais
18.
Nat Microbiol ; 4(3): 404-413, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30664667

RESUMO

Epstein-Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer1,2. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification1,2. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms3. Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF14-7, while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Deleção de Genes , Neoplasias Hematológicas/virologia , Herpesvirus Humano 4/genética , Transtornos Linfoproliferativos/virologia , Animais , Proteínas de Ligação a DNA/genética , DNA Polimerase Dirigida por DNA/genética , Feminino , Xenoenxertos , Humanos , Proteínas Imediatamente Precoces/genética , Masculino , Camundongos , MicroRNAs/genética , Pessoa de Meia-Idade , Mutação , Processos Neoplásicos , Transativadores/genética , Proteínas Virais/genética
20.
Lab Invest ; 99(4): 483-498, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30487595

RESUMO

Polyploid giant cancer cells (PGCCs) are key contributors to cancer heterogeneity, and the formation of PGCCs is associated with changes in the expression of cell-cycle-related proteins. This study investigated the intracellular localization and expression level of multiple cell-cycle-related proteins in PGCCs derived from BT-549 and HEY cells. In addition, the formation of PGCCs and the clinicopathological significance of cell-cycle-related proteins in human breast and ovarian cancer were examined. The expression levels of cell-cycle-related proteins, including cyclin B1, CDC25B, CDC25C, and other cell cycle phosphoproteins, including Chk2, and Aurora-A kinase, were determined using immunostaining and western blotting both in vitro and in vivo. Migration, invasion, and proliferation in control cells, cyclin B1 knockdown cells and their PGCCs following CoCl2 treatment were compared. In addition, human breast and ovarian cancer samples were collected to determine the correlation of number of PGCCs, expression of cell-cycle-related proteins, and tumor pathologic grade and metastasis. Our results confirm that cyclin B1 was localized in the cytoplasm of PGCCs and in the nuclei of their budding daughter cells. The phosphorylated proteins Chk2 and Aurora-A kinase regulated the expression and subcellular localization of cyclin B1, CDC25B, and CDC25C. The rate of positive cytoplasmic staining of cyclin B1 and positive nuclear staining of both CDC25B and CDC25C increased with increase in tumor grade and lymph node metastasis. Cell-cycle-related proteins, including cyclin B1, CDC25B, and CDC25C play an important role in regulating the formation of PGCCs. The inhibition of cyclinB1 and CoCl2 treatment significantly promoted cell proliferation, invasion, and migration abilities. The subcellular localization of these cell-cycle-related proteins was regulated by other cell cycle phosphoproteins, and was associated with pathologic grade and metastasis of tumors in cases of human breast and ovarian cancer.


Assuntos
Neoplasias da Mama , Proteínas de Ciclo Celular/metabolismo , Ciclina B1/metabolismo , Neoplasias Ovarianas , Fosfatases cdc25/metabolismo , Neoplasias da Mama/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Proteínas de Ciclo Celular/análise , Linhagem Celular Tumoral , Ciclina B1/análise , Feminino , Humanos , Espaço Intracelular/metabolismo , Processos Neoplásicos , Neoplasias Ovarianas/química , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/fisiopatologia , Poliploidia , Fosfatases cdc25/análise
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