Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.594
Filtrar
1.
Nat Commun ; 11(1): 4858, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978382

RESUMO

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.


Assuntos
Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores Tumorais , Quimioterapia Adjuvante , Cisplatino/uso terapêutico , Metilação de DNA , Tratamento Farmacológico , Instabilidade Genômica , Humanos , Mutação , Terapia Neoadjuvante , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transcriptoma , Neoplasias da Bexiga Urinária/patologia
2.
Gene ; 757: 144924, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32622992

RESUMO

OBJECTIVE: N-acetyltransferase 2 (NAT2) polymorphism could participate in the metabolism of carcinogens through regulating the activity of a series of critical enzymes. However, the effects of NAT2 polymorphism on bladder cancer (BCa) risk were still inconclusive. In order to illustrate whether NAT2 polymorphism may influence the susceptibility to BCa, we conducted this updated meta-analysis. MATERIALS AND METHODS: Databases including PubMed, Medline, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure(CNKI) were systematically retrieved and we applied MetaGenyo to perform final meta-analysis. Odds ratios (ORs) as well as 95% confidence intervals (CIs) were calculated and Bonferroni method was applied to correct the P-value for multiple comparisons. The registration of this study protocol is at PROSPERO and ID is CRD42019133957. RESULTS: Ultimately, 54 case-control studies were identified for final meta-analysis (13343 BCa cases and 18,586 controls). Overall analysis indicated that the slow genotype in NAT2 polymorphism was obviously associated with BCa risk (PBonferroni < 0.001). Subgroup analyses demonstrated that significant risk with the slow genotype was observed in Caucasians, Asians, smokers, non-exposed individuals, high grade bladder cancer (HGBC) patients and muscle-invasive bladder cancer (MIBC) patients. In addition, the intermediate NAT2 genotype was revealed to increase the BCa risk of Asians and transitional cell carcinoma (TCC) patients. However, no correlation was identified in Africans with the NAT2 polymorphism. CONCLUSIONS: The slow NAT2 genotype was identified to be the risk genotype for BCa. The intermediate genotype could serve as the candidate risk genotype. The gene-smoking interaction with NAT2 polymorphism might accelerate the tumor progression.


Assuntos
Arilamina N-Acetiltransferase/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Bexiga Urinária/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Fumar/epidemiologia , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/etnologia
3.
Medicine (Baltimore) ; 99(28): e21059, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664121

RESUMO

LncRNA plasmacytoma variant translocation 1 (PVT1) has been recognized as an oncogenic lncRNA, which participates in the migration and invasion of many kinds of cancer cells and the development of cancers. In the present study, we explored its clinical significance and prognostic value in muscle invasive bladder cancer (MIBC).A total of 98 MIBC patients' samples were collected, who had undergone radical cystectomy from the March 2013 to December 2018. The associations between PVT1 expression and clinical data were calculated using the Chi-test. Overall survival curves were determined by the Kaplan-Meier technique and contrasted via log-rank test. We utilized univariate and multivariate Cox proportional hazard models to examine the HR and 95% CI.The expression levels of PVT1 were significantly higher in MIBC tissues than that in normal bladder tissues (P < .001). PVT1 expression was significantly correlated with tumor grade (P = .009), margin (P = .002), T stage (P = .02), and lymph node metastasis (P < .001). MIBC patients with high PVT1 expression level had shorter overall survival than those with low PVT1 expression level (log-rank test, P = .004). Multivariate Cox regression analysis showed that PVT1 expression level (HR = 2.381, 95% CI: 1.821-7.012, P = .014) was an independent factor in predicting the overall survival of MIBC patients.In summary, increased PVT1 expression in MIBC patients is correlated with a higher MIBC stage and is significantly associated with poor prognosis for MIBC patients, which may provide new insights into new therapeutic strategy and postoperative intervention against bladder cancer.


Assuntos
RNA Longo não Codificante/biossíntese , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Idoso , Biomarcadores Tumorais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Regulação para Cima
4.
Cancer Sci ; 111(9): 3397-3400, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32678492

RESUMO

We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Forkhead Box O1/genética , Inativação Gênica , Neoplasias da Bexiga Urinária/genética , Proteína Forkhead Box O1/metabolismo , Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
5.
PLoS One ; 15(6): e0233676, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484812

RESUMO

In urothelial cell type non-muscle invasive urinary bladder carcinoma, TNM stage and WHO grade are widely used to classify patients into low and high­risk groups for prognostic and therapeutic decision-making. However, stage and grade reproducibility and prediction accuracy are wanting. This may lead to suboptimal treatment. We evaluated whether proliferation features, nuclear area of the epithelial cancer cells and the composition of stromal and tumor infiltrating lymphocytes have independent prognostic value. In 183 primary non-muscle invasive bladder cancer patients with long follow-up (median for stage progression cohort: 119 months, range 5-173; median for tumor recurrence cohort: 82, range 3-165) proliferation features Ki67, PPH3 and Mitotic Activity Index (MAI), Mean Nuclear Area (MNA), lymphocyte subsets (CD8+, CD4+, CD25+) and plasma cells (CD138+) were assessed on consecutive sections. Post-resection instillation treatments (none, mitomycin, BCG) were strictly standardized during the intake period. Risk of recurrence was associated with expression of Ki67 (≤ 39 vs. > 39) and Multifocality (p = 0.01). Patients with low Ki67 had a higher recurrence rate than those with high Ki67. Lymphocyte composition did not predict recurrence. Stage progression was strongly associated with high values for MAI (>15) and CD25+ (>0.2%). In a multivariate analysis the combination of MAI and CD25+ was the single most prognostic feature (p<0.001). Validation of these results in additional, independent studies is warranted.


Assuntos
Carcinoma de Células de Transição/patologia , Linfócitos do Interstício Tumoral/imunologia , Índice Mitótico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos Testes , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/mortalidade
6.
Analyst ; 145(12): 4173-4180, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32490854

RESUMO

Studies have shown that microRNAs, which are small noncoding RNAs, hold tremendous promise as next-generation circulating biomarkers for early cancer detection via liquid biopsies. A novel, solid-state nanoplasmonic sensor capable of assaying circulating microRNAs through a combined surface-enhanced Raman scattering (SERS) and plasmon-enhanced fluorescence (PEF) approach has been developed. Here, the unique localized surface plasmon resonance properties of chemically-synthesized gold triangular nanoprisms (Au TNPs) are utilized to create large SERS and PEF enhancements. With careful modification to the surface of Au TNPs, this sensing approach is capable of quantifying circulating microRNAs at femtogram/microliter concentrations. Uniquely, the multimodal analytical methods mitigate both false positive and false negative responses and demonstrate the high stability of our sensors within bodily fluids. As a proof of concept, microRNA-10b and microRNA-96 were directly assayed from the plasma of six bladder cancer patients. Results show potential for a highly specific liquid biopsy method that could be used in point-of-care clinical diagnostics to increase early cancer detection or any other diseases including SARS-CoV-2 in which RNAs can be used as biomarkers.


Assuntos
MicroRNA Circulante/sangue , Corantes Fluorescentes/química , Análise Espectral Raman , Neoplasias da Bexiga Urinária/diagnóstico , Betacoronavirus/isolamento & purificação , Biomarcadores Tumorais/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Ouro/química , Humanos , Limite de Detecção , Microscopia Confocal , Nanoestruturas/química , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Sistemas Automatizados de Assistência Junto ao Leito , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
8.
DNA Cell Biol ; 39(6): 1072-1089, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32352838

RESUMO

The roof plate-specific spondin (RSPO) family of proteins has critical roles in the tumorigenesis and progression of several carcinomas; however, little is known about their functions in bladder cancer (BLCA). This study aimed to investigate RSPO in terms of their expression levels, prognostic value, and potential mechanisms of action in BLCA. mRNA expression profiles and clinical information of BLCA patients were collected from The Cancer Genome Atlas database. Genetic alteration and DNA methylation data were obtained from cBioPortal and MethHC databases, respectively, and SurvExpress was used to determine the prognostic risk score of each RSPO. R software was used to analyze the expression levels and prognostic roles of RSPOs in BLCA. The effects of RSPO2 overexpression in BLCA cells were detected using MTT, colony formation, and Transwell invasion assays. Gene set enrichment analysis (GSEA) was used to analyze the functions of RSPOs and associated signaling pathways in BLCA. All members of the RSPO family were differentially expressed in BLCA cells compared with normal control cells. Aberrant RSPO expression levels were associated with higher histological stages and worse prognosis. The frequency of genetic alterations in RSPO genes was very high, which was related to a less favorable prognosis. Moreover, the effects of mutations in the RSPO2 gene were reversed using a Wnt/ß-catenin inhibitor, IWP-2. In addition, GSEA demonstrated that RSPOs were associated with focal adhesion and immune cell infiltration, which was then confirmed by tumor immune cell infiltration analysis. RSPOs are potential biomarkers for predicting the prognosis of patients with BLCA and may serve as novel therapeutic targets. Moreover, overexpressed RSPO2 promoted BLCA cell growth and invasion through the Wnt/ß-catenin pathway. In addition, RSPOs may regulate the progression of BLCA through modulating cell adhesion, focal adhesion, and CD4+ T cell and macrophage infiltration.


Assuntos
Regulação Neoplásica da Expressão Gênica , Trombospondinas/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Linhagem Celular Tumoral , Metilação de DNA , Humanos , Mutação , Prognóstico , RNA Mensageiro/genética , Análise de Sobrevida
9.
Medicine (Baltimore) ; 99(19): e19980, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384449

RESUMO

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with bladder cancer (BCa) risk in Caucasian and East Asian population. The objective of this study was to validate these SNPs in Chinese population and evaluate whether these SNPs could differentiate the individual inherited risk for BCa.A case-control study including 581 BCa cases and 1561 healthy controls was performed. Germline DNA samples from all individuals were genotyped for eight SNPs. Genetic risk score (GRS) was calculated for each individual based on the odds ratios and risk allele frequencies of five risk-associated SNPs.Among eight SNPs evaluated in this study, rs798766 at 4p16.3 [OR = 1.39 (1.15-1.67), P < .001], rs9642880 [OR = 1.17 (1.06-1.30), P < .001] and rs4813953 at 20p12.2 [OR = 1.09 (1.02-1.17), P = .016] were found associated with BCa risk in Chinese population. A genetic risk score was established based on five SNPs (including the above three SNPs and two other SNPs which have the consistent direction with previous reported genome-wide association study). The mean GRS was significantly higher in BCa cases than controls (1.22 vs. 1.01, P < .001). When subjects were categorized into low- (<0.8), average- (0.8-1.2), and high-risk (>1.2) groups, the likelihoods of BCa were 25.2%, 33.7% and 55.0%, respectively (P-trend < 2.2 × 10). In subgroup analyses, no significant difference was observed in mean GRS among BCa patients with different stages or grades.In conclusion, two SNPs derived from East Asian and one SNP from Caucasian were associated with BCa risk in Chinese population. These results provided additional information of genetic risks for BCa in Chinese population. Genetic risk score based on these SNPs can reveal inherited risk of BCa, and may have potential for modifying personalized cancer screening strategy.


Assuntos
Predisposição Genética para Doença/etnologia , Proteínas Associadas aos Microtúbulos/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Medição de Risco/métodos , Neoplasias da Bexiga Urinária/etnologia , Neoplasias da Bexiga Urinária/genética
10.
Cancer Sci ; 111(7): 2423-2430, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32350965

RESUMO

The transmembrane receptors integrins are the bridges for cell-cell or cell-ECM interaction, which is strictly correlated to cancer development in several tumor types. Here, we revealed that integrin ß8 serves as a driver to mediate sustained growth of bladder cancer and development of drug resistance. The elevated expression of integrin ß8 was observed in highly malignant bladder tumor tissues from patients. The in vitro and in vivo results further indicated that integrin ß8 overexpression in Biu87/T24 bladder cancer could mediate and strengthen cell proliferation and resistance to mitomycin C and hydroxycamptothecin. Mechanistically, integrin ß8 on the cellular surface might recruit phosphorylated Y-box binding protein 1, leading to the activation of c-Myc and nuclear factor-κB signals. Pharmacological targeting of integrin ß8 by Arg-Gly-Asp-Ser efficiently suppressed sustained growth and drug resistance in bladder cancer cells. Our findings identified integrin ß8 as a marker of bladder cancer diagnosis and development, and provides an innovative approach for clinical bladder cancer therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Cadeias beta de Integrinas/metabolismo , Transdução de Sinais , Neoplasias da Bexiga Urinária/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Cadeias beta de Integrinas/genética , Camundongos , NF-kappa B/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Proteína 1 de Ligação a Y-Box/genética
11.
Nat Commun ; 11(1): 2540, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439865

RESUMO

Tumor heterogeneity is common in cancer, however recent studies have applied single gene expression signatures to classify bladder cancers into distinct subtypes. Such stratification assumes that a predominant transcriptomic signature is sufficient to predict progression kinetics, patient survival and treatment response. We hypothesize that such static classification ignores intra-tumoral heterogeneity and the potential for cellular plasticity occurring during disease development. We have conducted single cell transcriptome analyses of mouse and human model systems of bladder cancer and show that tumor cells with multiple lineage subtypes not only cluster closely together at the transcriptional level but can maintain concomitant gene expression of at least one mRNA subtype. Functional studies reveal that tumor initiation and cellular plasticity can initiate from multiple lineage subtypes. Collectively, these data suggest that lineage plasticity may contribute to innate tumor heterogeneity, which in turn carry clinical implications regarding the classification and treatment of bladder cancer.


Assuntos
Linhagem da Célula/genética , Plasticidade Celular/genética , Neoplasias da Bexiga Urinária/patologia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Integrina alfa6/genética , Integrina alfa6/metabolismo , Queratina-5/genética , Queratina-5/metabolismo , Camundongos , Fenótipo , Análise de Célula Única , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo
12.
Cancer Sci ; 111(7): 2349-2360, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32449280

RESUMO

Solute carrier family 12 member 5 (SLC12A5) has an oncogenic role in bladder urothelial carcinoma. The present study aimed to characterize the molecular mechanisms of SLC12A5 in bladder urothelial carcinoma pathogenesis. Functional assays identified that in bladder urothelial carcinoma SLC12A5 interacts with and stabilizes SOX18, and then upregulates matrix metalloproteinase 7 (MMP7). In vivo and in vitro assays were performed to confirm the effect of SLC12A5's interaction with SOX18 on MMP7-mediated bladder urothelial carcinoma progression. SLC12A5 was upregulated in human bladder tumors, and correlated with the poor survival of patients with bladder urothelial carcinoma tumor invasion and metastasis, promoted by SLC12A5 overexpression. We demonstrated that SLC12A5 interacted with SOX18, and then upregulated MMP7, thus enhancing tumor progression. Importantly, SLC12A5 expression correlated positively with SOX18 and MMP7 expression in bladder urothelial carcinoma. Furthermore, SLC12A5 expression was suppressed by miR-133a-3p. Ectopic expression of SLC12A5 partly abolished miR-133a-3p-mediated suppression of cell migration. SLC12A5-SOX18 complex-mediated upregulation on MMP7 was important in bladder urothelial carcinoma progression. The miR-133a-3p/SLC12A5/SOX18/MMP7 signaling axis was critical for progression, and provided an effective therapeutic approach against bladder urothelial carcinoma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Metaloproteinase 7 da Matriz/genética , Fatores de Transcrição SOXF/metabolismo , Simportadores/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 7 da Matriz/metabolismo , Pessoa de Meia-Idade , Prognóstico , Ligação Proteica , Transdução de Sinais , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
13.
Proc Natl Acad Sci U S A ; 117(22): 12288-12294, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32430334

RESUMO

PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti-PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole-genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti-PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti-PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti-PD-L1 monotherapy in bladder cancer.


Assuntos
Pele/imunologia , Neoplasias da Bexiga Urinária/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Autoimunidade , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Estudos de Coortes , Humanos , Herança Multifatorial , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Pele/efeitos dos fármacos , Células Th17/imunologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
14.
Med Sci Monit ; 26: e920504, 2020 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-32277695

RESUMO

BACKGROUND Evidence indicates that there is an important role for long non-coding RNAs (lncRNA) in numerous cellular processes and that lncRNAs dysregulation contributes to tumor progression. Improved insight into the molecular characteristics of bladder cancer is required to predict outcomes and to develop a new rationale for targeted therapeutic strategies. Bioinformatics methods, including functional enrichment and network analysis combined with survival analysis, are required to process a large volume of data to obtain further information about differentially expressed genes (DEGs) in bladder cancer. This study aimed to explore the role of lncRNAs and their regulation network in bladder cancer. MATERIAL AND METHODS We analyzed bladder cancer data by The Cancer Genome Atlas profiling to identify differentially expressed lncRNAs in bladder cancer. The genes involved in the circlncRNAnet database were evaluated using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), evolutionary relationship analysis, and protein-protein interaction (PPI) networks. RESULTS Two new lncRNAs, ADAMTS9-AS1 and LINC00460, were shown to be differentially expressed in bladder cancer. Patients were divided into 2 groups (high expression and low expression) according to their median expression values. The overall survival and disease-free survival of patients with high ADAMTS9-AS1 bladder cancer were significantly shorter; the expression of LINC00460 had no significant correlation with survival. GO and KEGG analysis of the 2 lncRNA-related genes revealed that these lncRNAs played a vital role in tumorigenesis. Bioinformatics analysis showed that key genes related to LINC00460, including CXCL, CCL, and CSF2, may be related to the development of bladder cancer. The low expression of ADAMTS9-AS1 may influence the survival rate of bladder cancer with the hub gene as a target. CONCLUSIONS LncRNA, including LINC00460 and ADAMTS9-AS1, might play a crucial role in the biosynthesis network of bladder cancer. Differential expression results of ADAMTS9-AS1 suggests it may be correlated with a worse prognosis and a shorter survival time. We outlined the biosynthesis network that regulates lncRNAs in bladder cancer. Further experimental data is needed to validate our results.


Assuntos
RNA Longo não Codificante/genética , Neoplasias da Bexiga Urinária/genética , Biomarcadores Tumorais/genética , Biologia Computacional , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Prognóstico , Mapas de Interação de Proteínas , Análise de Sobrevida , Transcriptoma , Neoplasias da Bexiga Urinária/diagnóstico
15.
Anticancer Res ; 40(4): 2011-2017, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234891

RESUMO

BACKGROUND/AIM: We aimed to examine the association of the genotypes of Nijmegen breakage syndrome 1 (NBS1), a critical gene in DNA double strand break repair machinery, with bladder cancer risk in Taiwan. MATERIALS AND METHODS: NBS1 rs1805794 genotypes among 375 bladder cancer patients and 375 non-cancer healthy controls were determined via the polymerase chain reaction-restriction fragment length polymorphism methodology and their association with bladder cancer risk were evaluated. RESULTS: The results showed that the percentages of GG, CG and CC of NBS1 rs1805794 genotypes were 45.4%, 43.7% and 10.9% in the bladder cancer patient group and 47.2%, 43.2% and 9.6% in the non-cancer control group, respectively (p for trend=0.7873). The analysis of allelic frequency distributions showed that the variant C allele of NBS1 rs1805794 does not contribute to an increased bladder cancer susceptibility (p=0.5066). CONCLUSION: The genotypes of NBS1 rs1805794 are not closely associated with personal susceptibility to bladder cancer.


Assuntos
Proteínas de Ciclo Celular/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas Nucleares/genética , Neoplasias da Bexiga Urinária/genética , Alelos , Reparo do DNA/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/patologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Neoplasias da Bexiga Urinária/patologia
16.
Am J Pathol ; 190(8): 1752-1762, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32339497

RESUMO

The biological processes of urothelial carcinogenesis are not fully understood, particularly regarding the relationship between specific genetic events, cell of origin, and molecular subtypes of subsequent tumors. N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced mouse bladder cancer is widely accepted as a useful model that recapitulates the pathway of human bladder tumorigenesis from dysplasia to invasive cancer via carcinoma in situ. However, the long and variable time of tumorigenesis often hinders efficient preclinical or translational research. We hypothesized that Trp53 mutation in specific types of urothelial cells facilitates efficient development of clinically relevant bladder cancer. Using lineage tracing, we showed that Trp53 mutation in Krt5-expressing cells resulted in more efficient tumorigenesis of mouse muscle-invasive bladder cancer (MIBC) with squamous differentiation compared with Trp53 mutation in Upk2-expressing cells, or wild-type or hemizygous Trp53 in the entire urothelium. Mouse MIBC that developed at 24 weeks of BBN treatment showed morphologic and genetic similarities to the basal squamous subtypes of human MIBC, irrespective of pre-induction of Trp53 mutation or whether the cell of origin was Krt5- or Upk2-expressing cells. Our findings suggest that intermediate cells as well as basal cells also can give rise to basal-like MIBC, with pre-induction of Trp53 mutation accelerating MIBC. Thus, in BBN chemical carcinogenesis, pre-induction of Trp53 mutation in basal cells facilitates efficient modeling of the basal squamous subtype of human MIBC.


Assuntos
Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células de Transição/genética , Queratina-5/genética , Proteína Supressora de Tumor p53/genética , Neoplasias da Bexiga Urinária/genética , Bexiga Urinária/patologia , Animais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células de Transição/metabolismo , Carcinoma de Células de Transição/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Regulação Neoplásica da Expressão Gênica , Queratina-5/metabolismo , Camundongos , Mutação , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
17.
Zhonghua Yi Xue Za Zhi ; 100(16): 1249-1254, 2020 Apr 28.
Artigo em Chinês | MEDLINE | ID: mdl-32344498

RESUMO

Objective: To examine the expression of long-chain non-coding RNA (lncRNA) FLJ37505 in bladder cancer tissues and cell lines, and to analyze the molecular mechanism of FLJ37505 to inhibit the proliferation and migration of bladder cancer cells. Methods: Quantitative Real-time PCR(qPCR) was used to analyze the relative expression of FLJ37505 in 63 cases of bladder cancer tissues and bladder cancer cell lines (T24, J82, 5637, BIU-87 and UM-UC-3). The bladder cancer cell lines with the least expression of FLJ37505 were divided into control group (transfected with blank plasmid) and FLJ37505 group (transfected with a plasmid carrying the FLJ37505 sequence) according to random number method. MTS assay and scratch assay were used to detect the effect of up-regulation of FLJ37505 expression on cell proliferation and migration. Bioinformatics predicts the target gene of FLJ37505. The dual luciferase reporter system detects the binding of FLJ37505 to the target gene. qPCR and Western blot were used to detect the effect of FLJ37505 on the expression of target gene. Results: Compared with adjacent tissues, FLJ37505 expression was lower in bladder cancer tissue [(4.90±0.79) vs (0.89±0.28), P<0.05]. Compared with human normal bladder tubular epithelial cells, the expression of FLJ37505 was lower in bladder cancer cell lines (P<0.05), and FLJ37505 has the lowest expression in UM-UC-3 cells (P<0.01). Compared with the control group, the expression of FLJ37505 in UM-UC-3 cells of FLJ37505 group was higher [(0.79±0.04) vs (9.92±1.17), P<0.01]. Compared with the control group, the proliferation ability of UM-UC-3 cells in FLJ37505 group was inhibited (P<0.05), and the cell migration ability was also inhibited (P<0.01). Bioinformatics showed that the target gene of FLJ37505 is miR-203a-3p, and the target gene of miR-203a-3p is inositol polyphosphate 4-phosphatase typeⅡ (INPP4B). The dual luciferase reporter gene system showed that FLJ37505 could complement the miR-203a-3p (P<0.01), and miR-203a-3p could complement the INPP4B mRNA (P<0.01). Compared with the control group, the expression of miR-203a-3p was lower [(1.00±0.05) vs (0.20±0.02), P<0.01], the expression of INPP4B in mRNA and protein levels of UM-UC-3 cells in FLJ37505 group was significantly increased (all P<0.01). Conclusions: The expression of FLJ37505 was significantly decreased in bladder cell carcinoma and bladder cancer cells. Up-regulation of FLJ37505 significantly inhibits the proliferation and migration of bladder cell carcinoma UM-UC-3 cells, and the mechanism might be up-regulating the expression of the INPP4B gene by adsorbing miR-203a-3p.


Assuntos
Neoplasias da Bexiga Urinária , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Células Epiteliais , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Longo não Codificante , Neoplasias da Bexiga Urinária/genética
18.
Nat Commun ; 11(1): 1975, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332851

RESUMO

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.


Assuntos
Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia , Idoso , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Biópsia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Feminino , Perfilação da Expressão Gênica , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoconjugados/farmacologia , Subunidade gama Comum de Receptores de Interleucina/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Transplante de Neoplasias , Fenótipo , Medicina de Precisão , Estudos Prospectivos , Quinolinas/farmacologia , Estudos Retrospectivos , Análise de Sequência de RNA
20.
Cancer Commun (Lond) ; 40(4): 167-180, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32279463

RESUMO

BACKGROUND: The preoperative prediction of muscular invasion status is important for adequately treating bladder cancer (BC) but nevertheless, there are some existing dilemmas in the current preoperative diagnostic accuracy of BC with muscular invasion. Here, we investigated the potential association between the fluorescence in situ hybridization (FISH) assay and muscular invasion among patients with BC. A cytogenetic-clinical nomogram for the individualized preoperative differentiation of muscle-invasive BC (MIBC) from non-muscle-invasive BC (NMIBC) is also proposed. METHODS: All eligible BC patients were preoperatively tested using a FISH assay, which included 4 sites (chromosome-specific centromeric probe [CSP] 3, 7, and 17, and gene locus-specific probe [GLP]-p16 locus). The correlation between the FISH assay and BC muscular invasion was evaluated using the Chi-square tests. In the training set, univariate and multivariate logistic regression analyses were used to develop a cytogenetic-clinical nomogram for preoperative muscular invasion prediction. Then, we assessed the performance of the nomogram in the training set with respect to its discriminatory accuracy and calibration for predicting muscular invasion, and clinical usefulness, which were then validated in the validation set. Moreover, model comparison was set to evaluate the discrimination and clinical usefulness between the nomogram and the individual variables incorporated in the nomogram. RESULTS: Muscular invasion was more prevalent in BC patients with positive CSP3, CSP7 and CSP17 status (OR [95% CI], 2.724 [1.555 to 4.774], P < 0.001; 3.406 [1.912 to 6.068], P < 0.001 and 2.483 [1.436 to 4.292], P = 0.001, respectively). Radiology-determined tumor size, radiology-determined clinical tumor stage and CSP7 status were identified as independent risk factors of BC muscular invasion by the multivariate regression analysis in the training set. Then, a cytogenetic-clinical nomogram incorporating these three independent risk factors was constructed and was observed to have satisfactory discrimination in the training (AUC 0.784; 95% CI: 0.715 to 0.853) and validation (AUC 0.743; 95% CI: 0.635 to 0.850) set. The decision curve analysis (DCA) indicated the clinical usefulness of our nomogram. In models comparison, using the receiver operator characteristic (ROC) analyses, the nomogram showed higher discriminatory accuracy than any variables incorporated in the nomogram alone and the DCAs also identified the nomogram as possessing the highest net benefits at wide range of threshold probabilities. CONCLUSION: CSP7 status was identified as an independent factor for predicting muscular invasion in BC patients and was successfully incorporated in a clinical nomogram combining the results of the FISH assay with clinical risk factors.


Assuntos
Cromossomos Humanos Par 7/metabolismo , Hibridização in Situ Fluorescente/métodos , Neoplasias da Bexiga Urinária/genética , Idoso , Aneuploidia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA