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1.
HLA ; 97(2): 127-132, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33179437

RESUMO

The coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by SARS-CoV-2. Since its first report in December 2019, COVID-19 has evolved into a global pandemic causing massive healthcare and socioeconomic challenges. HLA system is critical in mediating anti-viral immunity and recent studies have suggested preferential involvement of HLA-B in COVID-19 susceptibility. Here, by investigating the HLA-B genotypes in 190 unrelated Chinese patients with confirmed COVID-19, we identified a significant positive association between the B22 serotype and SARS-CoV-2 infection (p = 0.002, Bonferroni-corrected p = 0.032). Notably, the B22 serotype has been consistently linked to susceptibility to other viral infections. These data not only shed new insights into SARS-CoV-2 pathogenesis and vaccine development but also guide better infection prevention/control.


Assuntos
COVID-19/genética , COVID-19/imunologia , Antígenos HLA-B/genética , SARS-CoV-2 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , COVID-19/epidemiologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Antígenos HLA-B/classificação , Teste de Histocompatibilidade , Hong Kong/epidemiologia , Humanos , Fenômenos Imunogenéticos , Masculino , Pessoa de Meia-Idade , Pandemias , Índice de Gravidade de Doença , Adulto Jovem
2.
J Cell Mol Med ; 24(22): 13523-13535, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33074587

RESUMO

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated epithelial malignancy. The high expression of BART-miRNAs (miR-BARTs) during latent EBV infection in NPC strongly supports their pathological importance in cancer progression. Recently, we found that several BART-miRNAs work co-operatively to modulate the DNA damage response (DDR) by reducing Ataxia-telangiectasia-mutated (ATM) activity. In this study, we further investigated the role of miR-BARTs on DDR. The immunohistochemical study showed that the DNA repair gene, BRCA1, is consistently down-regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role of BART2-3p, BART12, BART17-5p and BART19-3p in BRCA1 expression. The ectopic expression of these four miR-BARTs suppressed endogenous BRCA1 expression in EBV-negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenous miR-BARTs activities in C666-1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines using miR-BART17-5p and miR-BART19-3p mimics reduced the DNA repair capability and increased the cell sensitivity to the DNA-damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest that miR-BARTs play a novel role in DDR and may facilitate the development of effective NPC therapies.


Assuntos
Proteína BRCA1/genética , Resistencia a Medicamentos Antineoplásicos/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , MicroRNAs , Carcinoma Nasofaríngeo/etiologia , RNA Viral , Animais , Proteína BRCA1/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Interações Hospedeiro-Patógeno/genética , Humanos , Imuno-Histoquímica , Camundongos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/etiologia , Neoplasias Nasofaríngeas/patologia , Interferência de RNA
4.
Clin Lymphoma Myeloma Leuk ; 18(7): e315-e325, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29807803

RESUMO

BACKGROUND: Previous studies in Western countries demonstrated BRAF V600E mutation only in a small subset of multiple myeloma (MM) patients. However, the prevalence and clinicopathologic significances of this mutation remain unclear in Chinese MM patients. PATIENTS AND METHODS: We studied diagnostic bone marrow samples from 205 Chinese MM patients by allele-specific PCR to detect BRAF V600E mutation and by high-resolution melting assay to detect KRAS and NRAS mutations. The mutations were confirmed by independent assays. RESULTS: BRAF V600E mutation was found in 9.3% of the cases, the highest prevalence hitherto reported. In addition, the mutation was significantly associated with hypercalcemia and a male predominance but not with aggressive extramedullary diseases or a high serum creatinine level as reported in Western studies. Importantly, BRAF V600E mutation was an adverse prognostic factor for overall survival in younger MM patients by subgroup analysis. Concurrent analysis of RAS mutations highlighted differential alteration spectrum of RAS signaling between Chinese and Western MM, which may suggest a unique myeloma-related genetic profile in Chinese patients. CONCLUSION: Our study revealed a higher prevalence of BRAF V600E mutation in Chinese MM patients. The associated prognostic impacts on younger patients could be beneficial to risk stratification and potential application of BRAF-targeted therapies in Chinese MM management. This is the first large-scale study revealing the prevalence and clinicopathologic significances of BRAF V600E mutation in Chinese myeloma.


Assuntos
Substituição de Aminoácidos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Biomarcadores Tumorais , China/epidemiologia , Análise Mutacional de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/mortalidade , Prevalência , Proteínas ras/genética
6.
Hemoglobin ; 41(4-6): 283-285, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29043885

RESUMO

We report a novel HBB: c.114G>C mutation in a Chinese family. This mutation resulted in a ß37(C3)Trp→Cys amino acid substitution and was synonymous with Hb Kent, a hemoglobin (Hb) variant that was reported exclusively in patients of European descent. Though Hb Kent has a normal oxygen affinity and molecular stability, it has a characteristic dual variant appearance on cellulose acetate electrophoresis (CAE) and high performance liquid chromatography (HPLC) caused by the posttranslational modification of cysteine. We also report the phenotypic expression of this variant when coinherited with the Southeast Asian (- -SEA) double α-globin gene deletion.


Assuntos
Hemoglobinas Anormais/genética , Mutação de Sentido Incorreto , Adulto , Substituição de Aminoácidos , Povo Asiático , China , Família , Feminino , Hemoglobinas Anormais/metabolismo , Humanos , Masculino
7.
Exp Cell Res ; 350(1): 199-209, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27908592

RESUMO

Previously, we reported that GPR30 activation by the receptor-specific, non-estrogenic ligand G-1 inhibited in vitro and in vivo growth of prostate cancer (PCa) cells via sustained Erk1/2 activation. Mechanism underlying the sustained Erk1/2 activation for PCa cell growth inhibition remains unclear. Here we report that G-1, through GPR30, activated Gαi1 proteins to sustain Erk1/2 activation but failed to activate adenylyl cyclase (AC) for cAMP production in PCa cells. The chemical-induced activation of AC-cAMP-PKA signaling attenuated Erk1/2 activity and blocked the cell growth inhibitory effects of G-1. Furthermore, PCa predominantly expressed Gαi1 proteins. Silencing of Gαi1 expression blocked the inhibitory effects of G-1 on PCa cell growth. By gene expression profiling, GPR30 activation by G-1 interfered expression of cell cycle regulators and machinery elements to modulate PCa cell growth and the RACGAP1 interactome to control metastatic properties. In this regard, we demonstrated that G-1 inhibited PCa cell migration and invasion with reduced formations of filopodia and stress fibers through a GPR30-dependent pathway. Taken together, our findings revealed the underlying mechanism for sustaining Erk1/2 activation upon GPR30 activation by G-1 in PCa cells and the GPR30-mediated pathways in controlling PCa cell growth and metastatic properties.


Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adenilil Ciclases/metabolismo , Ciclo Celular/fisiologia , Proliferação de Células/fisiologia , Estrogênios/metabolismo , Humanos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
8.
Hemoglobin ; 40(6): 400-404, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27707011

RESUMO

Genetic association studies showed that Hb F is under the influence of major quantitative trait loci (QTL) in ß-thalassemia (ß-thal) carriers. Single nucleotide polymorphisms (SNPs) at three major QTLs, BCL11A, HBS1L-MYB intergenic region and XmnI-HBG2 were individually validated in univariate models. However, their relative effect sizes on Hb F regulation are unknown. We genotyped 99 Chinese ß-thal carriers for the three major QTLs and performed genetic association studies using three different statistical models, including mass univariate analysis, multivariate linear regression and partial least square regression structural equation modeling (PLS-SEM). Performances of the three models were compared and effect sizes of the three QTLs in a multivariate model were assessed. Traditional mass univariate analysis and multivariate linear regression showed limited statistical power in our small cohort and the latter was constrained by multicollinearity. Partial least structural equation modeling showed significant positive associations of each QTL (p <0.05) with Hb F regulation, together explained 34.4% of variance. The HBS1L-MYB intergenic region polymorphism (HMIP) demonstrated the highest effect on Hb F prediction with effect size f2 0.294. PLS-SEM offered a statistically powerful multivariate model for multi-locus genetic association studies. We reproduced findings of previous studies with a much smaller cohort and demonstrated HMIP as the strongest regulator of Hb F in Chinese ß-thal carriers.


Assuntos
Hemoglobina Fetal/metabolismo , Heterozigoto , Locos de Características Quantitativas , Talassemia beta/genética , Adulto , Povo Asiático , DNA Intergênico/genética , Feminino , Proteínas de Ligação ao GTP/genética , Proteínas de Choque Térmico HSP70/genética , Humanos , Masculino , Modelos Estatísticos , Fatores de Alongamento de Peptídeos/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-myb/genética
9.
Int J Mol Sci ; 17(9)2016 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-27589731

RESUMO

Prostate cancer (PCa) treatment was first established by Huggins and Hodges in 1941, primarily described as androgen deprivation via interference of testicular androgen production. The disease remains incurable with relapse of hormone-refractory cancer after treatments. Epidemiological and clinical studies disclosed the importance of estrogens in PCa. Discovery of estrogen receptor ERß prompted direct estrogenic actions, in conjunction with ERα, on PCa cells. Mechanistically, ERs upon ligand binding transactivate target genes at consensus genomic sites via interactions with various transcriptional co-regulators to mold estrogenic signaling. With animal models, Noble revealed estrogen dependencies of PCa, providing insight into potential uses of antiestrogens in the treatment. Subsequently, various clinical trials were conducted and molecular and functional consequences of antiestrogen treatment in PCa were delineated. Besides, estrogens can also trigger rapid non-genomic signaling responses initiated at the plasma membrane, at least partially via an orphan G-protein-coupled receptor GPR30. Activation of GPR30 significantly inhibited in vitro and in vivo PCa cell growth and the underlying mechanism was elucidated. Currently, molecular networks of estrogenic and antiestrogenic signaling via ERα, ERß and GPR30 in PCa have not been fully deciphered. This crucial information could be beneficial to further developments of effective estrogen- and antiestrogen-based therapy for PCa patients.


Assuntos
Moduladores de Receptor Estrogênico/uso terapêutico , Estrogênios/metabolismo , Neoplasias da Próstata/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais , Animais , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico
10.
Int J Clin Exp Pathol ; 8(9): 11945, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26617952

RESUMO

Medulloblastoma (MB) is the most common malignant brain tumor in children. Although multimodality treatment regimens including surgery, radiotherapy and chemotherapy have greatly improved disease outcome, about one-third of MB patient remains incurable, and many long-term survivors are suffered from deleterious effects due to aggressive treatment. Understanding the signaling pathways and the genetic mechanisms contributed to MB development would be the key to develop novel therapeutic treatment strategies for improving survival and outcome of MB. In this review, we discuss the biological signaling pathways involved in MB pathogenesis. We also go through the current international consensus of four core MB subgroups namely, SHH, WNT, Group 3 and Group 4. This is adopted based on the knowledge of genomic complexity of MB as analyzed by recent high-throughput genomic technology. We talk about immunohistochemistry assays established to determine molecular subgroup affiliation. In the last part of review, we discuss how identification of molecular subgroups is going to change our routine disease diagnosis and clinical management.

11.
PLoS One ; 10(5): e0127910, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26009886

RESUMO

Many facets of the tumor biology of medulloblastoma (MB) have not been fully elucidated. Collapsin response mediator protein 1 (CRMP1) is a member of cytoplasmic family of proteins that regulate the development of central nervous system. Recent studies demonstrated that CRMP1 could function as an invasion suppressor. We reported previously that high mobility group AT-hook 1 (HMGA1) contributed to development of MB and regulated its growth and migration/invasion. Transcriptional profiling and quantitative RT-PCR revealed increased expression of CRMP1 in HMGA1-depleted cells, suggesting that CRMP1 may be a downstream target of HMGA1 in MB. In this study, we showed HMGA1 can bind CRMP1 promoter by chromatin immunoprecipitation (ChIP) assay. Luciferase assay demonstrated a marked enhancement of CRMP1 transcription activity in HMGA1-depleted cells. Furthermore, quantitative RT-PCR revealed a negative correlation between HMGA1 and CRMP1 in 32 MB samples. To investigate the biological roles of CRMP1 in MB pathogenesis, we established MB clones stably expressing CRMP1. Functional analysis revealed that expression of CRMP1 significantly inhibited proliferation, migration, invasion and formation of filopodia and intense stress fiber of MB cells. Our data suggest that HMGA1 regulates CRMP1 expression and CRMP1 is implicated in MB pathogenesis.


Assuntos
Neoplasias Cerebelares/metabolismo , Proteína HMGA1a/metabolismo , Meduloblastoma/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Adolescente , Adulto , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteína HMGA1a/genética , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Adulto Jovem
12.
Neuropathol Appl Neurobiol ; 41(2): 145-64, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25041637

RESUMO

AIMS: MicroRNAs (miRNAs) are an abundant group of small non-coding RNAs that have been implicated in tumorigenesis. They regulate expression of target genes by complementary base pairing. The purposes of this study were to delineate miR-106b expression in medulloblastoma (MB) and to explore its functional contributions to MB pathogenesis. METHODS: We analysed expression of miR-106b in 32 MB samples by quantitative RT-PCR. We applied gain- and loss-of-function strategies to delineate the functional roles of miR-106b in MB. Luciferase reporter assay was conducted to confirm target gene of miR-106b. RESULTS: Expression of miR-106b was overexpressed in MB, and was significantly associated with its host gene MCM7 (P = 0.020). Transfection of miR-106b inhibitor in MB cell lines markedly reduced cell proliferation, migration and invasion potential, and tumour sphere formation. Cell cycle analysis indicated that miR-106b inhibition induced G1 arrest and apoptosis. The cell cycle regulators, p21 and cyclin D1, and apoptotic marker cleaved PARP were differentially expressed in miR-106b inhibitor-transfected cells. PTEN was identified as a direct target gene of miR-106b. Luciferase reporter assay confirmed miR-106b directly interacted with the 3' UTR of PTEN. We found miR-106b directly targeted PTEN at transcriptional and translational levels. Immunohistochemistry revealed a trend between PTEN and miR-106b in MB tumours (P = 0.07). CONCLUSIONS: These data suggested the upregulation of miR-106b in MB and the involvement of miR-106b in MB biology.


Assuntos
Neoplasias Cerebelares/genética , Regulação Neoplásica da Expressão Gênica/genética , Meduloblastoma/genética , MicroRNAs/biossíntese , PTEN Fosfo-Hidrolase/metabolismo , Adolescente , Adulto , Western Blotting , Linhagem Celular Tumoral , Neoplasias Cerebelares/metabolismo , Criança , Feminino , Humanos , Imuno-Histoquímica , Masculino , Meduloblastoma/metabolismo , MicroRNAs/análise , Reação em Cadeia da Polimerase em Tempo Real , Transfecção , Regulação para Cima , Adulto Jovem
13.
J Cell Physiol ; 230(8): 1906-15, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25546515

RESUMO

Benign prostatic hyperplasia (BPH) is a hyper-proliferative disease of the aging prostate; however, the exact mechanism underlying the development of BPH remains incompletely understood. The present study investigated the possible involvement of the cystic fibrosis transmembrane conductance regulator (CFTR), which has been previously shown to negatively regulate nuclear factor-κB (NF-κB)/cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) pathway, in the pathogenesis of BPH. Our results showed decreasing CFTR and increasing COX2 expression in rat prostate tissues with aging. Furthermore, suppression of CFTR led to increased expression of COX2 and over-production of PGE2 in a normal human prostate epithelial cell line (PNT1A) with elevated NF-κB activity. PGE2 stimulated the proliferation of primary rat prostate stromal cells but not epithelial cells, with increased PCNA expression. In addition, the condition medium from PNT1A cells after inhibition or knockdown of CFTR promoted cell proliferation of prostate stromal cells which could be reversed by COX2 or NF-κB inhibitor. More importantly, the involvement of CFTR in BPH was further demonstrated by the down-regulation of CFTR and up-regulation of COX2/NF-κB in human BPH samples. The present results suggest that CFTR may be involved in regulating PGE2 production through its negative regulation on NF-κB/COX2 pathway in prostate epithelial cells, which consequently stimulates cell growth of prostate stromal cells. The overstimulation of prostate stromal cell proliferation by down-regulation of CFTR-enhanced PGE2 production and release during aging may contribute to the development of BPH.


Assuntos
Envelhecimento/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/biossíntese , Hiperplasia Prostática/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/biossíntese , Modelos Animais de Doenças , Regulação para Baixo , Imunofluorescência , Humanos , Imuno-Histoquímica , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Transfecção
14.
J Transl Med ; 12: 281, 2014 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-25288334

RESUMO

BACKGROUND: Aberrant AKT activation contributes to gastric cancer cell survival and chemotherapy resistance, however its regulation is poorly understood. microRNAs have been established to be important regulators in gastric carcinogenesis. Here, we showed the functional role and putative target of let-7b and let-7g (let-7b/g) in gastric carcinogenesis. METHODS: The expression of let-7b/g in gastric cancer cell lines and primary tumors were evaluated by miRNA qRT-PCR. The putative target gene of let-7b/g was explored by TargetScan followed by further validation. Functional analyses including MTT proliferation, monolayer colony formation, cell invasion assays and in vivo study were performed in both ectopic expression and knockdown approaches. RESULTS: let-7b/g was found down-regulated in gastric cancer and its downregulation was associated with poor survival and correlated with lymph node metastasis. let-7b/g inhibited AKT2 expression by directly binding to its 3'UTR, reduced p-AKT (S473) activation and suppressed expression of the downstream effector pS6. AKT2 mRNA expression showed negative correlation with the expression of let-7b/g in primary tumors. Short interfering RNA (siRNA) mediated knockdown of AKT2 phenocopied the tumor-suppressive effects of let-7b/g. Moreover, AKT2 re-expression partly abrogated the growth-inhibitory effect of let-7b/g. CONCLUSION: In conclusion, our findings reveal decreased let-7b/g contributes to aberrant AKT activation in gastric tumorigenesis and provide a potential therapeutic strategy for gastric cancer.


Assuntos
Carcinogênese/genética , Carcinogênese/patologia , Inativação Gênica , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos Nus , Dados de Sequência Molecular , Ligação Proteica/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética , Análise de Sobrevida , Regulação para Cima
15.
Mol Cancer ; 13: 184, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-25098679

RESUMO

BACKGROUND: As a distinctive type of head and neck cancers, nasopharyngeal carcinoma (NPC) is genesis from the clonal Epstein-Barr virus (EBV)-infected nasopharyngeal epithelial cells accumulated with multiple genetic lesions. Among the recurrent genetic alterations defined, loss of 9p21.3 is the most frequent early event in the tumorigenesis of EBV-associated NPC. In addition to the reported CDKN2A/p16, herein, we elucidated the role of a miRNA, miR-31 within this 9p21.3 region as NPC-associated tumor suppressor. METHODS: The expression and promoter methylation of miR-31 were assessed in a panel of NPC tumor lines and primary tumors. Its in vitro and in vivo tumor suppression function was investigated through the ectopic expression of miR-31 in NPC cells. We also determined the miR-31 targeted genes and its involvement in the growth in NPC. RESULTS: Downregulation of miR-31 expression was detected in almost all NPC cell line, patient-derived xenografts (PDXs) and primary tumors. Both homozygous deletion and promoter hypermethylation were shown to be major mechanisms for miR-31 silencing in this cancer. Strikingly, loss of miR-31 was also obviously observed in the dysplastic lesions of nasopharynx. Restoration of miR-31 in C666-1 cells inhibited the cell proliferation, colony-forming and migratory capacities. Dramatic reduction of in vitro anchorage-independent growth and in vivo tumorigenic potential were demonstrated in the stable clones expressing miR-31. Furthermore, we proved that miR-31 suppressed the NPC cell growth via targeting FIH1 and MCM2. CONCLUSIONS: The findings provide strong evidence to support miR-31 as a new NPC-associated tumor suppressor on 9p21.3 region. The inactivation of miR-31 may contribute to the early development of NPC.


Assuntos
Carcinogênese/patologia , Herpesvirus Humano 4/fisiologia , MicroRNAs/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/virologia , Carcinogênese/genética , Carcinoma , Movimento Celular/genética , Proliferação de Células , Sobrevivência Celular/genética , Hibridização Genômica Comparativa , Metilação de DNA/genética , Regulação para Baixo/genética , Deleção de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Homozigoto , Humanos , MicroRNAs/genética , Componente 2 do Complexo de Manutenção de Minicromossomo/metabolismo , Oxigenases de Função Mista/metabolismo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Fosforilação , Regiões Promotoras Genéticas , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/metabolismo
16.
PLoS One ; 9(7): e100793, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25014919

RESUMO

BACKGROUND: Evidence implicated the diagnostic significance of microRNAs in whole urine/urine sediments in urothelial carcinoma of the bladder (UCB). However, the contaminated blood cells in patients with haematouria significantly altered the expression profiles of urinary microRNA, influencing the test accuracy. METHODS: MicroRNA profiles of the urine supernatants of UCB patients and controls without any malignancy and profiles of malignant and corresponding normal mucosa tissues from the patients were determined by microRNA microarray and compared to identify differentially expressed microRNAs. The differential expression was verified in the tissues of an independent patient cohort by RT-qPCR. The diagnostic significance of selected microRNAs as biomarkers in the urine supernatant was investigated in the expanded cohorts. RESULTS: MicroRNA-99a and microRNA-125b were down-regulated in the urine supernatants of UCB patients. The degree of down-regulation was associated with the tumor grade. A diagnostic model was developed using a combined index of the levels of microRNA-99a and microRNA-125b in the urine supernatant with a sensitivity of 86.7%, a specificity of 81.1% and a positive predicted value (PPV) of 91.8%. Discriminating between high- and low-grade UCB, the model using the level of microRNA-125b alone exhibited a sensitivity of 81.4%, a specificity of 87.0% and a PPV of 93.4%. CONCLUSIONS: The results revealed a unique microRNA expression signature in the urine supernatants of UCB patients for the development of molecular diagnostic tests. An effective cell-free urinary microRNA-based model was developed using a combined index of the levels of microRNA-99a and microRNA-125b to detect UCB with good discriminating power, high sensitivity and high specificity.


Assuntos
Biomarcadores Tumorais/urina , MicroRNAs/urina , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade
17.
PLoS One ; 9(5): e98037, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24837491

RESUMO

Fulvestrant (ICI-182,780) has recently been shown to effectively suppress prostate cancer cell growth in vitro and in vivo. But it is unclear whether microRNAs play a role in regulating oncogene expression in fulvestrant-treated prostate cancer. Here, this study reports hsa-miR-765 as the first fulvestrant-driven, ERß-regulated miRNA exhibiting significant tumor suppressor activities like fulvestrant, against prostate cancer cell growth via blockage of cell-cycle progression at the G2/M transition, and cell migration and invasion possibly via reduction of filopodia/intense stress-fiber formation. Fulvestrant was shown to upregulate hsa-miR-765 expression through recruitment of ERß to the 5'-regulatory-region of hsa-miR-765. HMGA1, an oncogenic protein in prostate cancer, was identified as a downstream target of hsa-miR-765 and fulvestrant in cell-based experiments and a clinical study. Both the antiestrogen and the hsa-miR-765 mimic suppressed HMGA1 protein expression. In a neo-adjuvant study, levels of hsa-miR-765 were increased and HMGA1 expression was almost completely lost in prostate cancer specimens from patients treated with a single dose (250 mg) of fulvestrant 28 days before prostatectomy. These findings reveal a novel fulvestrant signaling cascade involving ERß-mediated transcriptional upregulation of hsa-miR-765 that suppresses HMGA1 protein expression as part of the mechanism underlying the tumor suppressor action of fulvestrant in prostate cancer.


Assuntos
Antineoplásicos Hormonais/farmacologia , Movimento Celular , Proliferação de Células , Estradiol/análogos & derivados , Antagonistas do Receptor de Estrogênio/farmacologia , MicroRNAs/metabolismo , Neoplasias da Próstata/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Linhagem Celular Tumoral , Estradiol/farmacologia , Estradiol/uso terapêutico , Antagonistas do Receptor de Estrogênio/uso terapêutico , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/metabolismo , Fulvestranto , Proteínas HMGA/genética , Proteínas HMGA/metabolismo , Humanos , Masculino , MicroRNAs/genética , Invasividade Neoplásica , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Regulação para Cima
18.
PLoS One ; 8(7): e69467, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23936021

RESUMO

Minimal residual disease, or MRD, is an important prognostic indicator in childhood acute lymphoblastic leukemia. In ALL-IC-BFM 2002 study, we employed a standardized method of flow cytometry MRD monitoring for multiple centers internationally using uniformed gating, and determined the relevant MRD-based risk stratification strategies in our local patient cohort. We also evaluated a novel method of PCR MRD quantitation using peripheral blood plasma. For the bone marrow flow MRD study, patients could be stratified into 3 risk groups according to MRD level using a single time-point at day-15 (Model I) (I-A: <0.1%, I-B: 0.1-10%, I-C: >10%), or using two time-points at day-15 and day-33 (Model II) (II-A: day-15<10% and day-33<0.01%, II-B: day-15 ≥ 10% or day-33 ≥ 0.01% but not both, II-C: day-15 ≥ 10% and day-33 ≥ 0.01%), which showed significantly superior prediction of relapse (p = .00047 and <0.0001 respectively). Importantly, patients with good outcome (frequency: 56.0%, event-free survival: 90.1%) could be more accurately predicted by Model II. In peripheral blood plasma PCR MRD investigation, patients with day-15-MRD ≥ 10(-4) were at a significantly higher risk of relapse (p = 0.0117). By multivariate analysis, MRD results from both methods could independently predict patients' prognosis, with 20-35-fold increase in risk of relapse for flow MRD I-C and II-C respectively, and 5.8-fold for patients having plasma MRD of ≥ 10(-4). We confirmed that MRD detection by flow cytometry is useful for prognostic evaluation in our Chinese cohort of childhood ALL after treatment. Moreover, peripheral blood plasma DNA MRD can be an alternative where bone marrow specimen is unavailable and as a less invasive method, which allows close monitoring.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , DNA de Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Antineoplásicos/administração & dosagem , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Humanos , Lactente , Masculino , Neoplasia Residual , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Recidiva , Risco
19.
Int J Clin Exp Pathol ; 6(7): 1211-22, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23826403

RESUMO

Medulloblastoma (MB) is the most common malignant brain tumor in children. Although multimodality treatment regimens including surgery, radiotherapy and chemotherapy have greatly improved disease outcome, about one-third of MB patient remains incurable, and many long-term survivors are suffered from deleterious effects due to aggressive treatment. Understanding the signaling pathways and the genetic mechanisms contributed to MB development would be the key to develop novel therapeutic treatment strategies for improving survival and outcome of MB. In this review, we discuss the biological signaling pathways involved in MB pathogenesis. We also go through the current international consensus of four core MB subgroups namely, SHH, WNT, Group 3, and Group 4. This is adopted based on the knowledge of genomic complexity of MB as analyzed by recent high-throughput genomic technology. We talk about immunohistochemistry assays established to determine molecular subgroup affiliation. In the last part of review, we discuss how identification of molecular subgroups is going to change our routine disease diagnosis and clinical management.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Cerebelares/genética , Meduloblastoma/genética , Transdução de Sinais/genética , Animais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Resistencia a Medicamentos Antineoplásicos , Predisposição Genética para Doença , Testes Genéticos , Genômica/métodos , Humanos , Meduloblastoma/classificação , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Terapia de Alvo Molecular , Seleção de Pacientes , Fenótipo , Medicina de Precisão , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
20.
Mol Carcinog ; 52 Suppl 1: E28-38, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22711332

RESUMO

A common GC polymorphism within miRNA-146a precursor region (rs2910164) has been associated with the risk of various cancers despite the underlying mechanism is unclear. In the current study, we aimed to examine the role of rs2910164 in the pathogenesis and predisposition to nasopharyngeal carcinoma (NPC). The GC polymorphism in 233 NPC patients, 173 matched controls and 3613 healthy elderly subjects in our locality were first determined using melting temperature (T(m))-shift allele-specific genotyping method. Results in our case-control study indicated that CC genotype was associated with the risk effect of NPC (adjusted odds ratio of GC + GG vs. CC, 0.49; 95% confidence interval, 0.35-0.69; P < 0.0001). Using real-time polymerase chain reaction (PCR) assay, we subsequently revealed that expressions of both miR-146a and its passenger strand (miR-146a*C or miR-146a*G) were increased in NPC samples (P < 0.001), albeit expression of miR-146a was not linked to the genotype. Furthermore, miR-146a*C in NPC was significantly increased in CC genotype (CC vs. GC, P = 0.038). Finally, we demonstrated by co-immunoprecipitation and luciferase reporter assays that all three miR-146a precursor-derived mature miRNAs interacted with Argonaute2 (Ago2) protein complex and could function as gene silencers. Taken together, our results showed that the variant C in rs2910164 was associated with the predisposition of NPC in Chinese population. This polymorphism may influence the risk of NPC by producing active mature miR-146a*C that regulate distinct set of target genes. These findings may enrich our understanding of how miRNA single nucleotide polymorphism affect NPC pathogenesis, and may have potential implications to improve NPC treatment in the future.


Assuntos
MicroRNAs/genética , Neoplasias Nasofaríngeas/etiologia , Polimorfismo de Nucleotídeo Único/genética , Idoso , Proteínas Argonautas/metabolismo , Biomarcadores Tumorais/genética , Carcinoma , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Imunoprecipitação , Luciferases/metabolismo , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Reação em Cadeia da Polimerase , Prognóstico , Fatores de Risco
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