Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.058
Filtrar
1.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 601-608, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699189

RESUMO

Objective To investigate the expression and clinical significance of late endosomal/lysosomal adaptor,mitogen-activated protein kinase and mammalian target of rapamycin activator 3(LAMTOR3)in bladder carcinoma.Methods Oncomine and Expression Atlas were used to extract the useful mining gene chip database for analyzing the expression of LAMTOR3 in bladder carcinoma tissues and cell lines,and the correlation of LAMTOR3 with the clinicopathological features were analyzed.RT-PCR,Western blot,and immunohistochemistry were performed to detect the expression of LAMTOR3 in bladder carcinoma cell lines,specimens,and adjacent normal tissues for verifying the results exploited from the above databases.Results The Expression Atlas showed that LAMTOR3 had high expressions in Hs172.T,HT-1376,RT4,JMSU-1,and T24 cell lines among 20 bladder carcinoma cell lines,among which the LAMTOR3 expression was different.Oncomine reported that LAMTOR3 expression in bladder carcinoma,including invasive(t=2.857,P=0.005)and non-invasive carcinoma(t=3.105,P=0.003),was significantly higher than that in adjacent normal tissues.The expression of LAMTOR3 was positively correlated with pathological grade(P<0.05).The expressions of LAMTOR3 mRNA in bladder carcinoma cell lines,including UMUC3(t=10.84,P=0.0084),J82(t=21.75,P=0.0021),5637(t=45.88,P=0.0005),and T24(t=87.58,P=0.0001)were significantly higher than that in normal bladder cell line SV-HUC-1,while its expression in bladder carcinoma tissues was significantly higher than that in adjacent normal tissues(P<0.05),so was its protein level in tissues(P<0.05).Immunohistochemistry showed that LAMTOR3 protein was over-expressed in bladder carcinoma tissues;its level in invasive carcinoma tissues was higher than that in no-invasive carcinoma tissues and was related closely with the clinical stages(χ 2=9.189,P=0.002),pathological grades(χ 2=4.746,P=0.029),and lymphatic metastasis(χ 2=6.210,P=0.013)but had no significant correlation to sex(χ 2=0.965,P=0.326),age(χ 2=2.126,P=0.145),and distant metastasis(χ 2=1.261,P=0.261).Conclusion LAMTOR3 is highly expressed in bladder carcinoma cell lines and tissues and plays a key role in the development and progression of bladder carcinoma.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Bexiga Urinária/genética , Linhagem Celular Tumoral , Humanos , Prognóstico , Neoplasias da Bexiga Urinária/patologia
2.
Anticancer Res ; 39(9): 4767-4773, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519577

RESUMO

BACKGROUND/AIM: Rs3824129 is a functional six-nucleotide insertion(I)/deletion(D) polymorphism in the promoter region of caspase 8, an essential apoptosis gene. We aimed to examine the association of this polymorphism with the risk of bladder cancer in the Taiwanese population. MATERIALS AND METHODS: Caspase-8 rs3834129 genotypes were determined and their associations with bladder cancer risk were evaluated among 375 patients and 375 controls by the PCR-RFLP methodology. In addition, the interaction of caspase-8 rs3834129 genotypes with personal behaviors and clinicopathological features were examined. RESULTS: The frequencies of II, ID and DD genotypes for caspase-8 rs3834129 were non-differentially distributed between the two groups (p for trend=0.7187). Analysis of allelic frequency distribution also indicated that the D variant allele was not associated with a risk of bladder cancer. There was no obvious joint interaction between caspase-8 rs3834129 genotypes and smoking, alcohol consumption, and clinical stage and grade. CONCLUSION: Caspase-8 rs3834129 genotypes play a minor role in the personal susceptibility to bladder cancer in Taiwan.


Assuntos
Caspase 8/genética , Predisposição Genética para Doença , Genótipo , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Razão de Chances , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Taiwan , Neoplasias da Bexiga Urinária/patologia
3.
J Cancer Res Clin Oncol ; 145(11): 2725-2736, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31552489

RESUMO

PURPOSE: The identification of biomarkers characterizing the invasive potential of bladder cancer could enhance the clinical management of individual patients and therefore improve prognosis. The aim of this study was to define a miRNA panel in tumor tissues as well as in urinary extracellular vesicles (EVs) for discriminating muscle-invasive bladder cancer (MIBC) from non-muscle-invasive bladder cancer (NMIBC). METHODS: miRNA expression was analyzed in 24 formalin-fixed, paraffin-embedded (FFPE) tumor samples by microarray analysis and was further validated by qRT-PCR in 56 FFPE tumor samples as well as in 37 urinary EV samples. RESULTS: Microarray analysis revealed 63 miRNAs that were significantly differentially expressed (P < 0.05) between tissues from MIBC and NMIBC tumors. Five selected miRNAs (miR-146b-5p, miR-155-5p, miR-138-5p, miR-144-5p, and miR-200a-3p) were validated by qRT-PCR. The expression of all except miR-144-5p was significantly associated with high tumor grade. In urinary EVs, a different expression was verified for miR-146b-5p (P = 0.004) and miR-155-5p (P = 0.036), which exhibited significantly higher expression in urinary EVs from patients with MIBC. CONCLUSIONS: miRNAs are promising biomarkers for the identification of invasive bladder carcinomas. Tissue samples as well as urinary EVs may serve as sources for miRNA analysis. This method, in addition to histopathology, could provide a new diagnostic tool and facilitate individual therapeutic decisions to select patients for early cystectomy.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/urina , Vesículas Extracelulares/genética , MicroRNAs/genética , MicroRNAs/urina , Neoplasias Musculares/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/genética , Neoplasias Musculares/urina , Prognóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/urina
4.
J Cancer Res Clin Oncol ; 145(11): 2649-2661, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31529191

RESUMO

PURPOSE: The incidence of Urothelial carcinoma of bladder (UBC) is gradually increasing by changing lifestyle and environment. The development of a tumor has been noted to be accompanied by modifications in the extracellular matrix (ECM) consisting of CD44, hyaluronic acid (HA) and its family members. The importance of CD44 splice variants and HA family members has been studied in UBC. METHODS: The cohort of study included 50 UBC patients undergoing radical cystectomy and 50 healthy subjects. The molecular expression of CD44 and HA family members was determined. Effect of CD44 variant-specific silencing on downstream signaling in HT1376 cells was investigated. Combinatorial treatment of 4-MU (4-methylumbelliferone) with cisplatin or doxorubicin on chemosensitivity was also explored. RESULTS: Higher expression of HA, HAS2, and CD44 was observed in Indian UBC patients which also showed the trend with severity of disease. Splice variant assessment of CD44 demonstrated the distinct role of CD44v3 and CD44v6 in bladder cancer progression. shRNA-mediated downregulation of CD44v3 showed an increase effect on cell cycle, apoptosis and multiple downstream signaling cascade including pAkt, pERK and pSTAT3. Furthermore, 4-MU, an HA synthesis inhibitor, observed to complement the effect of Cisplatin or Doxorubicin by enhancing the chemosensitivity of bladder cancer cells. CONCLUSIONS: Our findings exhibit involvement of CD44 splice variants and HA family members in UBC and significance of 4-MU in enhancing chemosensitivity suggesting their novel therapeutic importance in disease therapeutics.


Assuntos
Processamento Alternativo , Receptores de Hialuronatos/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias da Bexiga Urinária/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Apoptose , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Fator de Transcrição STAT3/genética , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
5.
Medicine (Baltimore) ; 98(32): e16451, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393349

RESUMO

Early diagnose of bladder cancer could lead to good prognosis and high 5-year-survival rate. Among bladder cancer, about 75% patients with were nonmuscle-invasive bladder cancer (NMIBC). Patients were painful and easily get infected during bladder cancer diagnosis, which mainly depends on invasive cystoscopy and low-sensitivity urine exfoliation cytology. Meanwhile, relapse after surgery was also becoming the major problem for patients. Exploring noninvasive, high-sensitivity, and painless method is very important and meaningful for NMIBC treatment.Firstly, we found potential related gene mutation sites for NMIBC by searching COSMIC database and related study. Urinary sediment cells of patients both in normal group (patients with benign) and NMIMC group were collected before and after operation for potential gene mutation site detecting. Meanwhile, the urinary sediment cells of relapse patients and good prognosis people in NMIBC group after surgery were also collected for further Gene mutation detection and NMIBC relapse after surgery prediction.Fourteen genes (152 mutation sites) were selected between 95 NMIBC patients and 67 control patients, which were FGFR3, TP53, PIK3CA, and others. Compared with control group, mutation ratio of above 14 genes was higher in NMIBC group. NMIBC diagnose model was established by 5 times cross-validation and had a good effects, which included the all mutation site in FGFR3, TP53, PIK3CA, ARID1A, STAG2, and KTM2D. On the contrary, the relapse rate was 30.5% among 95 patients for about 1.5-year follow-up time. Compared with control group, smoking rate and tumor grade were higher in relapse group. Meanwhile, mutation rate of FGFR3, TP53, PIK3CA, ERBB3, and TSC1 in relapse group were higher than that in normal group. According to the mutation sites of FGFR3, TP53, PIK3CA, and ERBB3 and the combination of urinary sediment cells genetic mutation and relapse status, a predicted model for NMIBC relapse was also established, which had 90% accuracy.The diagnosed NMIBC model (based on FGFR3, TP53, PIK3CA, ARID1A, STAG2, and KTM2D gene mutation) and predicted relapse model (based on FGFR3, TP53, PIK3CA, and ERBB3 gene mutation) possess high accuracy and would be applied in early diagnose and early predicting relapse of patients.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteína Supressora de Tumor p53/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia
6.
Beijing Da Xue Xue Bao Yi Xue Ban ; 51(4): 615-622, 2019 Aug 18.
Artigo em Chinês | MEDLINE | ID: mdl-31420610

RESUMO

OBJECTIVE: To construct the prognostic model and identify the prognostic biomarkers based on long non-coding RNA (lncRNA) in bladder cancer. METHODS: The lncRNA expression data and corresponding clinical data of bladder cancer were collected from The Cancer Genome Atlas (TCGA) database. The software Perl and R, and R packages were used for data integration, extraction, analysis and visualization. Detailly, R package "edgeR" was utilized to screen differentially expressed lncRNA in bladder cancer tissues compared with the normal bladder samples. The univariate Cox regression and the least absolute shrinkage and selection operator (Lasso) regression were performed to identify key lncRNA that were utilized to construct the prognostic model by the multivariate Cox regression. According to the median value of the risk score, all patients were divided into the high-risk group and low-risk group to perform the Kaplan-Meier (K-M) survival curves, receiver operating characteristic (ROC) curve and C-index, estimating the prognostic power of the prognostic model. In addition, the hazard ratio (HR) and 95% confidence interval (CI) of each key lncRNA were also calculated by the multivariate Cox regression. Moreover, we performed the K-M survival analysis for each significant key lncRNA from the result of the multivariate Cox regression. RESULTS: A total of 691 lncRNA were identified as differentially expressed lncRNA, and 35 lncRNA signatures were initially considered associated with the prognosis of bladder cancer, where in 23 lncRNA were identified as key lncRNA associated with the prognosis. The overall survival time in years of the low-risk group was obviously longer than that of the high-risk group [(2.85±2.72) years vs. (1.58±1.51) years, P<0.001]. The area under the ROC curve (AUC) was 0.813 (3-year survival) and 0.778 (5-year survival) respectively, and the C-index was 0.73. In addition, HR and 95%CI of each key lncRNA were calculated by the multivariate Cox regression and 11 lncRNA were significant. Furthermore, K-M survival analysis revealed the independent prognostic value of 3 lncRNA, including AL589765.1 (P=0.004), AC023824.1 (P=0.022)and PKN2-AS1 (P=0.016). CONCLUSION: The present study successfully constructed the prognostic model based on the expression level of 23 lncRNA and finally identified one protective prognostic biomarker AL589765.1, and two adverse prognostic biomarkers including AC023824.1 and PKN2-AS1 in bladder cancer.


Assuntos
Neoplasias da Bexiga Urinária , Biomarcadores Tumorais , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , RNA Longo não Codificante , Neoplasias da Bexiga Urinária/genética
7.
Medicine (Baltimore) ; 98(35): e16576, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464892

RESUMO

OBJECTIVES: G protein-coupled receptor 137 (GPR137) was reported to be associated with several cancers, but its role in bladder cancer has not been reported. The purpose of this study was to evaluate clinical significance of GPR137 in bladder cancer. METHODS: The expressions of GPR137 in pathological tissues and corresponding normal tissues from bladder cancer patients were detected via quantitative real time polymerase chain reaction (qRT-PCR). Western blot was performed to detect GPR137 expression in bladder cancer tissues and adjacent normal tissues. Chi-Squared test analyzed the relationship between GPR137 expression and clinical features of bladder cancer patients. Additionally, Kaplan-Meier method was adopted in estimating overall survival of bladder cancer patients. Prognostic value of GPR137 was evaluated through Cox regression analysis. RESULTS: The expression of GPR137 mRNA and protein in pathological tissues was significantly higher than that in adjacent normal tissues (P < .001). Moreover, similar result was found for bladder cancer patients and healthy controls (P < .001). And GPR137 expression was associated with tumor size (P = .006) and TNM stage (P = .012). The results of Kaplan-Meier analysis suggested that patients with high expression of GPR137 had shorter overall survival time than those with low expression (Log rank test, P = .001). Cox regression analysis indicated that GPR137 could act as an independent biomarker for bladder cancer prognosis (HR = 1.850, 95% CI = 1.272-2.689, P = .001). CONCLUSION: Abnormal expression of GPR137 is associated with bladder cancer and GPR137 is a potential biomarker for the therapy and prognosis of bladder cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Regulação para Cima , Neoplasias da Bexiga Urinária/metabolismo , Biomarcadores Tumorais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores Acoplados a Proteínas-G/genética , Análise de Sobrevida , Carga Tumoral , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
8.
Gene ; 719: 144077, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31454540

RESUMO

BACKGROUND: Glutathione S-transferases (GSTs) contain a series of critical enzymes regulating proliferation or apoptosis in the tumor microenvironment. Data from publications about the correlation between Glutathione S-transferase Pi 1 (GSTP1) gene 313 A/G (rs1695) polymorphism and bladder caner (BCa) remained controversial. To explore the exact correlation between this polymorphism and the development of BCa, we carried out this study. MATERIALS AND METHODS: All relevant publications from Pubmed, Web of Science, Cochrane Library, PMC, Embase and Wanfang databases (from building to March 30th, 2019) were retrieved. This meta-analysis was carried out by utilizing STATA software. RESULTS: 34 case-control studies with 15,704 participants recruiting 7236 BCa patients and 8468 healthy controls were ultimately analyzed in our study. The pooling results indicated that GSTP1 gene 313 A/G (rs1695) polymorphism was obviously related to BCa (GG vs AA: OR = 1.33, 95%CI = 1.04-1.69). Similar results were found in the association between this polymorphism and transitional cell carcinoma (TCC) risk (GG vs AA: OR = 1.95, 95%CI = 1.18-3.23). Furthermore, we revealed an increased association between the GG genotype and BCa in Asians (GG vs AA: OR = 2.04, 95%CI = 1.09-3.79), while no correlation was revealed in Caucasians. As to different tumor grades or stages, this polymorphism was considered to elevate low grade BCa development and null results were uncovered with high grade BCa. CONCLUSION: This study indicated that GSTP1 gene 313 A/G (rs1695) polymorphism increased the susceptibility to BCa, particularly to TCC. In addition, this study found that this polymorphism was obviously related to elevated BCa risk in Asian population and also increased low grade BCa risk. Results based on the five genetic models indicated that GSTP1 G-allele might be the susceptibility gene and GG genotype might be the susceptibility genotype.


Assuntos
Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Bexiga Urinária/genética , Estudos de Casos e Controles , Genótipo , Humanos
9.
Oncol Rep ; 42(4): 1609-1620, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364733

RESUMO

MicroRNAs (miRNAs/miRs) act as markers for various cancers, including bladder cancer (BC). Plasma miRNAs are potential biomarkers for the noninvasive diagnosis and long­term surveillance of BC. The aim of the present study was to identify diagnostically reliable miRNAs in the plasma and examine their potential monitoring capacity. miRNAs were measured by reverse transcription­quantitative polymerase chain reaction. The study was performed as a discovery phase, which included plasma samples from each of the 10 patients with and without BC prior to transurethral resection (TURB). The results were validated in a second phase, involving 36 patients with plasma samples collected before the second TURB or radical cystectomy (RC), and after RC. During the discovery step, three elevated miRNAs (miR­15b­5p, miR­590­5p, miR­29b­3p) and two decreased miRNAs (miR­10b­5p, miR­144­5p) were selected as potential miRNA candidates for further validation. miR­15b­5p and miR­590­5p were finally confirmed to discriminate between cancer cases and controls; however, for disease monitoring of BC, both miRNAs were not suitable as a decline in the miRNA levels was not observed in some patients after tumor removal. Our results suggested that circulating miR­15b­5p and miR­590­5p have useful diagnostic potential for BC, but are rather unsuitable as monitoring markers for disease. The reasons of this apparent contradictory observation may be due to the aspect of biological variation of circulating miRNAs and serial measurements could be unreliable.


Assuntos
Biomarcadores Tumorais/sangue , MicroRNAs/sangue , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Feminino , Voluntários Saudáveis , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Neoplasias da Bexiga Urinária/diagnóstico
10.
Oncol Rep ; 42(4): 1431-1440, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364745

RESUMO

Jumonji domain­containing protein 2A (JMJD2A) has been identified to promote cell proliferation in bladder cancer; however, it remains undetermined whether JMJD2A regulates cell migration and invasion in bladder cancer. The aim of the present study was to further investigate the roles of JMJD2A in bladder cancer. The expression levels of JMJD2A in bladder cancer tissues and cell lines were established by RT­qPCR assays and western blot analysis. Moreover, by gain­ and loss­of­function assays, the effects of JMJD2A on migration and invasion as well as proliferation were investigated in bladder cancer cells. The results revealed that the expression level of JMJD2A was significantly upregulated in bladder cancer tissues and cell lines compared to adjacent non­tumor tissues and a human immortalized bladder urothelial cell line. Kaplan­Meier survival analysis indicated that patients with high JMJD2A expression level had shorter overall survival. Moreover, JMJD2A could promote cell migration and invasion by facilitating epithelial­mesenchymal transition (EMT) in bladder cancer. In addition, it was determined that JMJD2A promoted EMT through regulation of SLUG expression. Collectively, our findings revealed that JMJD2A may act as an oncogene and participate in bladder cancer progression, which provides a promising therapeutic strategy for patients with bladder cancer.


Assuntos
Histona Desmetilases com o Domínio Jumonji/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transição Epitelial-Mesenquimal , Humanos , Histona Desmetilases com o Domínio Jumonji/biossíntese , Histona Desmetilases com o Domínio Jumonji/genética , Gradação de Tumores , Invasividade Neoplásica , Fatores de Transcrição da Família Snail/genética , Transcrição Genética , Regulação para Cima , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
11.
Cancer Sci ; 110(10): 3235-3243, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368627

RESUMO

Cytology is widely conducted for diagnosis of urothelial bladder cancer; however, its sensitivity is still low. Recent studies show that liquid biopsies can reflect tumor genomic profiles. We aim to investigate whether plasma or urine is more suitable for detecting tumor-derived DNA in patients with early-stage urothelial bladder cancer. Targeted sequencing of 71 genes was carried out using a total of 150 samples including primary tumor, urine supernatant, urine precipitation, plasma and buffy coat from 25 patients with bladder cancer and five patients with cystitis and benign tumor. We compared mutation profiles between each sample, identified tumor-identical mutations and compared tumor diagnostic sensitivities between urine and conventional cytology. We identified a total of 168 somatic mutations in primary tumor. In liquid biopsies, tumor-identical mutations were found at 53% (89/168) in urine supernatant, 48% (81/168) in urine precipitation and 2% (3/168) in plasma. The high variant allele fraction of urine was significantly related to worse clinical indicators such as tumor invasion and cytological examination. Although conventional cytology detected tumor cells in only 22% of non-invasive tumor, tumor diagnostic sensitivity increased to 67% and 78% using urine supernatant and precipitation, respectively. Urine is an ideal liquid biopsy for detecting tumor-derived DNA and more precisely reflects tumor mutational profiles than plasma. Genomic analysis of urine is clinically useful for diagnosis of superficial bladder cancer at early stage.


Assuntos
Biomarcadores Tumorais/urina , Mutação , Análise de Sequência de DNA/métodos , Neoplasias da Bexiga Urinária/diagnóstico , Urina/química , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Detecção Precoce de Câncer , Feminino , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/urina
12.
Life Sci ; 232: 116614, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260682

RESUMO

AIMS: SRY-box 18 (SOX18) is a transcription factor known for its role in regulating cell differentiation and lymphatic and blood vessel development. It has been reported that SOX18 was involved in various diseases, including cancer. This study aimed to explore the significance and biological function of SOX18 in bladder cancer (BCa). MATERIALS AND METHODS: SOX18 expression in BCa and normal tissues was analyzed by immunohistochemistry, and SOX18 expression in BCa cell lines was quantified by western blotting and quantitative real-time PCR. The role of SOX18 on the proliferation, migration and invasion of BCa cells was explored by CCK-8 and transwell invasion assays in vitro. Cell cycle was measured by flow cytometry assays. Western blotting and qRT-PCR were performed to investigate the potential mechanisms by which SOX18 leads to tumor progression. KEY FINDINGS: SOX18 was significantly upregulated in BCa and its expression was associated with clinical features of patients with BCa. Our data demonstrated that SOX18 promoted cell proliferation via accelerating cell cycle and by regulating c-Myc and Cyclin D1, promoted cell invasion via upregulation of MMP-7. Moreover, phosphorylation of c-Met and Akt regulated by SOX18 was identified to be involved in the process of cell migration and invasion, indicating the vital role of SOX18 in the metastasis of BCa. SIGNIFICANCE: Our data demonstrated a cancer-promoting effect of SOX18 in BCa, revealed the potential mechanisms of SOX18 in mediating cellular functions, and indicated that SOX18 may serve as a promising progression and prognostic biomarker and a therapeutic target for BCa.


Assuntos
Fatores de Transcrição SOXF/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Ciclina D1/metabolismo , Feminino , Fase G1/fisiologia , Xenoenxertos , Humanos , Masculino , Metaloproteinase 7 da Matriz/metabolismo , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fase S/fisiologia , Fatores de Transcrição SOXF/biossíntese , Fatores de Transcrição SOXF/genética , Transcriptoma/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
13.
Medicine (Baltimore) ; 98(27): e16009, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277094

RESUMO

Bladder cancer is one of the most common malignancies of urinary tract. The current study aimed to investigate the role of insulin-like growth factor II messenger RNA binding protein 3 (IMP3) expression in the prognostic evaluation of non-muscle- invasive urothelial carcinoma of the bladder.Immunohistochemistry (IHC) was carried out to examine IMP3 protein expression in specimens from 183 cases of non-muscle-invasive urothelial carcinoma, 20 cases of muscle-invasive urothelial carcinoma and 20 benign tissues adjacent to cancer tissue.The expression of IMP3 was not detected in the adjacent benign tissues. The expression intensity of IMP3 in muscle-invasive samples was significantly higher than that in non-muscle-invasive urothelial carcinoma specimens (P = .008). IMP3 expression was significantly related with advanced tumor stage (P < .001), advanced tumor grade (P = .004), and tumor recurrence (P < .001) in non-muscle-invasive urothelial carcinomas. Kaplan-Meier analysis showed that IMP3-positive patients had much lower disease-free (P < .001), progression-free (P = .002) and metastasis-free (P = .019) survival rates compared with those with IMP3-negative tumors. By multivariable Cox analysis, we also found that IMP3 expression in non-muscle- invasive urothelial carcinomas proved to be an independent unfavorable prognostic factor of disease-free survival (HR: 2.52; 95% CI, 1.39-4.56; P = .002), progression- free survival (HR: 5.19; 95% CI, 1.54-17.46; P = .008) and metastasis-free survival (HR: 4.87; 95% CI, 1.08-22.02; P = .040).Our results demonstrate that the expression of IMP3 in non-muscle- invasive bladder cancer can serve as an independent predictor that will help recognize the subgroup of patients with a high ability to relapse, progress, and metastasize and who might get the maximum benefit from an early and more aggressive treatment strategy.


Assuntos
Carcinoma de Células de Transição/genética , Proteínas de Ligação a RNA/genética , Neoplasias da Bexiga Urinária/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Modelos de Riscos Proporcionais , Proteínas de Ligação a RNA/metabolismo , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia
14.
Nat Cell Biol ; 21(8): 978-990, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31358969

RESUMO

Although 5-methylcytosine (m5C) is a widespread modification in RNAs, its regulation and biological role in pathological conditions (such as cancer) remain unknown. Here, we provide the single-nucleotide resolution landscape of messenger RNA m5C modifications in human urothelial carcinoma of the bladder (UCB). We identify numerous oncogene RNAs with hypermethylated m5C sites causally linked to their upregulation in UCBs and further demonstrate YBX1 as an m5C 'reader' recognizing m5C-modified mRNAs through the indole ring of W65 in its cold-shock domain. YBX1 maintains the stability of its target mRNA by recruiting ELAVL1. Moreover, NSUN2 and YBX1 are demonstrated to drive UCB pathogenesis by targeting the m5C methylation site in the HDGF 3' untranslated region. Clinically, a high coexpression of NUSN2, YBX1 and HDGF predicts the poorest survival. Our findings reveal an unprecedented mechanism of RNA m5C-regulated oncogene activation, providing a potential therapeutic strategy for UCB.


Assuntos
5-Metilcitosina/metabolismo , Regulação da Expressão Gênica/genética , Metiltransferases/genética , Neoplasias da Bexiga Urinária/genética , Proteína 1 de Ligação a Y-Box/genética , Animais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/metabolismo , Humanos , Camundongos , RNA Mensageiro/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
15.
Urologiia ; (1): 126-130, 2019 Apr.
Artigo em Russo | MEDLINE | ID: mdl-31184030

RESUMO

In the article the main mechanisms of molecular pathogenesis of urinary tract urothelial carcinoma are presented. Two different molecular pathways that determine the development of non-invasive and invasive urothelial carcinoma, the immunohistochemical spectrum of stem markers and aspects of the carcinogenesis of multifocal and recurrent tumors are considered.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Sistema Urinário , Neoplasias Urológicas , Biomarcadores , Carcinoma de Células de Transição/genética , Humanos , Recidiva Local de Neoplasia , Neoplasias da Bexiga Urinária/genética
16.
Urologe A ; 58(7): 760-767, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31172245

RESUMO

BACKGROUND: Molecular tumor boards (MTB) are becoming more common. There are several molecular alterations in urothelial cancer a molecular tumor board can potentially rely on. OBJECTIVES: The aim is to specify molecular alterations and their correlations with different clinical endpoints and to highlight potential questions addressed to a MTB for urothelial cancer. MATERIALS AND METHODS: Descriptive review of the literature based on PubMed. RESULTS: The landscape of molecular alterations in urothelial cancer is heterogeneous. Thus, recent biomarker research has been focusing on biomarker panels and classifiers instead of single biomarkers. Recently, molecular subtypes of urothelial cancer have been identified and correlated with different clinical endpoints. Furthermore, circulating tumor cells and tumor DNA are under investigation as potential biomarkers. In addition to treatment response and prognosis, molecular markers are also needed to improve clinical staging prior to radical cystectomy or for proper patient selection for neoadjuvant chemotherapy. Erdafitinib is the first targeted therapy (fibroblast growth factor receptor [FGFR] alteration) in urothelial cancer that was recently approved (in the USA). CONCLUSIONS: Due to the lack of external validation, none of the identified biomarkers is currently established in clinical routine. In addition, there is no single driver mutation in urothelial cancer that facilitates the development of biomarkers and targeted therapies.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células de Transição/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias Urológicas/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células de Transição/genética , Cistectomia , Humanos , Mutação , Terapia Neoadjuvante , Prognóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias Urológicas/genética
17.
J Agric Food Chem ; 67(28): 7844-7854, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31241937

RESUMO

Bladder cancer is the fourth common cancer among men and more than 70% of the bladder cancer is nonmuscle invasive bladder cancer (NMIBC). Because of its high recurrence rate, NMIBC brings to patients physical agony and high therapy costs to the patients' family and society. It is imperative to seek a natural compound to inhibit bladder cancer cell growth and prevent bladder cancer recurrence. Cell proliferation is one of the main features of solid tumor development, and the rapid tumor cell growth usually leads to hypoxia due to the low oxygen environment. In this study we found that sulforaphane, a natural chemical which was abundant in cruciferous vegetables, could suppress bladder cancer cells proliferation in hypoxia significantly stronger than in normoxia (p < 0.05): 20 µM sulforaphane inhibited bladder cancer cell proliferation by 26.1 ± 4.1% in normoxia, while it inhibited cell proliferation by 39.7 ± 5.2% in hypoxia in RT112 cells. Consistently, sulforaphane inhibited cell proliferation by 29.7 ± 4.6% in normoxia, while it inhibited cell proliferation by 48.3 ± 5.2% in hypoxia in RT4 cells. Moreover, we revealed that sulforaphane decreased glycolytic metabolism in a hypoxia microenvironment by downregulating hypoxia-induced HIF-1α and blocking HIF-1α trans-localization to the nucleus in NMIBC cell lines. This study discovered a food sourced compound inhibiting bladder cancer cells proliferation and provided experimental evidence for developing a new bladder cancer preventive and therapeutic strategy.


Assuntos
Proliferação de Células/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/fisiopatologia , Isotiocianatos/administração & dosagem , Neoplasias da Bexiga Urinária/fisiopatologia , Linhagem Celular Tumoral , Glicólise/efeitos dos fármacos , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/genética , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo
18.
BMC Cancer ; 19(1): 604, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31216997

RESUMO

BACKGROUND: The prognosis of bladder urothelial carcinoma (BLCA) varies greatly among patients, and conventional pathological predictors are generally inadequate and often inaccurate to predict the heterogeneous behavior of BLCA. This study aims to investigate the prognostic value and function of TOP2A in BLCA. METHODS: TOP2A expression level was examined by RNA-sequencing, quantitative real time polymerase chain reaction and immunohistochemistry from 10, 40 and 209 BLCA samples, respectively. Public databases were analyzed for validation. Cell proliferation, migration, invasion assays were performed to explore potential functions of TOP2A in BLCA. Flow cytometry was performed for cell cycle and apoptosis analysis. Univariable and multivariable Cox regression models were performed to identify independent risk factors for the prognosis of BLCA. RESULTS: We found TOP2A was significantly upregulated in BLCA samples, especially for high-grade and advanced stage tumors, compared with matched normal epithelial tissue. Univariable COX regression analysis revealed high TOP2A expression was significantly associated with poorer cancer-specific, progression-free and recurrence-free survival, but not independently of clinical characteristics in the multivariable models. Knockdown of TOP2A remarkably inhibited the proliferation of BLCA cells and non-cancerous urothelial cells. Furthermore, migration and invasion capacity of BLCA cells were strongly suppressed after TOP2A knockdown. Moreover, flow cytometry suggested TOP2A had anti-apoptotic function, and knockdown of TOP2A could induce resistance to doxorubicin in J82 cells. CONCLUSIONS: In our study, TOP2A was overexpressed in BLCA and could serve as a prognostic biomarker for BLCA. Moreover, TOP2A is functionally important for the proliferation, invasion and survival of BLCA cells.


Assuntos
Carcinoma/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Idoso , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células , DNA Topoisomerases Tipo II/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose/genética , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sequência de RNA , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
19.
BMC Cancer ; 19(1): 636, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253132

RESUMO

BACKGROUND: Muscle-invasive bladder tumors are associated with a high risk of relapse and metastasis even after neoadjuvant chemotherapy and radical cystectomy. Therefore, further therapeutic options are needed and molecular characterization of the disease may help to identify new targets. The aim of this study was to characterize muscle-invasive bladder tumors at the molecular level using computational analyses. METHODS: The TCGA cohort of muscle-invasive bladder cancer patients was used to describe these tumors. Probabilistic graphical models, layer analyses based on sparse k-means coupled with Consensus Cluster, and Flux Balance Analysis were applied to characterize muscle-invasive bladder tumors at a functional level. RESULTS: Luminal and Basal groups were identified, and an immune molecular layer with independent value was also described. Luminal tumors showed decreased activity in the nodes of epidermis development and extracellular matrix, and increased activity in the node of steroid metabolism leading to a higher expression of the androgen receptor. This fact points to the androgen receptor as a therapeutic target in this group. Basal tumors were highly proliferative according to Flux Balance Analysis, which makes these tumors good candidates for neoadjuvant chemotherapy. The Immune-high group showed a higher degree of expression of immune biomarkers, suggesting that this group may benefit from immune therapy. CONCLUSIONS: Our approach, based on layer analyses, established a Luminal group candidate for therapy with androgen receptor inhibitors, a proliferative Basal group which seems to be a good candidate for chemotherapy, and an immune-high group candidate for immunotherapy.


Assuntos
Carcinoma de Células de Transição/classificação , Carcinoma de Células de Transição/genética , Neoplasias da Bexiga Urinária/classificação , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma de Células de Transição/metabolismo , Carcinoma de Células de Transição/terapia , Matriz Extracelular/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Invasividade Neoplásica , Receptores Androgênicos/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/terapia
20.
Biochim Biophys Acta Gene Regul Mech ; 1862(8): 822-833, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31167152

RESUMO

Muscle invasive bladder cancer (MIBC) is characterized by a poor overall survival rate in patients. Therefore, innovation and evaluation of idea anti-cancer compounds is of importance for reducing the mortality of MIBCs. The chemotherapeutic activity of ChlA-F, a novel C8 fluoride derivative of cheliensisin A with potent anti-neoplastic properties, was barely investigated. We reported here that ChlA-F treatment significantly induced miR-494 expression and suppressed cell invasion in human MIBC cells. Our results indicated that miR-494 was downregulated in M1 metastatic BC patients in comparison to non-metastatic (M0) BC patients, and such downregulation was also well correlated with over survival rate for MIBC patients. Mechanistically, ChlA-F-induced upregulation of miR-494 was due to a HuR-mediated increase in JunB mRNA stabilization and protein expression, which led to an increase in miR-494 transcription via directly binding to the miR-494 promoter region, while the upregulated miR-494 was able to bind the 3'-UTR region of c-Myc mRNA, resulting in decreased c-Myc mRNA stability and protein expression and further reducing the transcription of c-Myc-regulated MMP-2 and ultimately inhibiting BC invasion. Our results provide the first evidence showing that miR-494 downregulation was closely associated with BC metastatic status and overall BC survival, and ChlA-F was able to reverse the level of miR-494 with a profound inhibition of human BC invasion in human invasive BC cells. Our studies also reveal that ChlA-F is a promising therapeutic compound for BCs and miR-494 could also serve as a promising therapeutic target for the treatment of MIBC patients.


Assuntos
Proteína Semelhante a ELAV 1/metabolismo , Lactonas/farmacologia , MicroRNAs/genética , Metástase Neoplásica/genética , Fatores de Transcrição/metabolismo , Neoplasias da Bexiga Urinária/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Metástase Neoplásica/tratamento farmacológico , Prognóstico , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/genética , Estabilidade de RNA/efeitos dos fármacos , Análise de Sobrevida , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA