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1.
Acta Cytol ; 64(1-2): 182-192, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31060038

RESUMO

Aside from its diagnostic importance, urinary tract endoscopy is an uncomfortable, expensive, and time-consuming procedure. Patients with a history of urothelial carcinoma remain at an increased risk for recurrence and the development of de novo disease; most have had exposure to carcinogenic risk factors for decades prior to their first diagnosis that have bathed the entire urothelial tract. Consequently, monitoring these patients over their lifetime has made urothelial carcinoma one of the most expensive cancers for the US healthcare system. This expense has provided a financial incentive for academic and commercial groups to develop a test with a sufficient negative predictive value to reduce the frequency of surveillance procedures. Slide-based tests require a separate slide prepared from a split urine sample or from an additional urinary tract specimen. This process can place an additional burden on the laboratory due to changes in the workflow, especially if the split specimens need to be stored until a cytologic diagnosis is rendered (i.e., when used as a reflex test). Importantly, slide-based tests allow for the result to be directly correlated with cytomorphologic findings; however, these tests require the cells of interest to be present. Thus, slide-based tests suffer from the same sensitivity issues as urinary tract cytology. In contrast, slide-free tests do not require an additional slide to be prepared, and laboratory testing may be centralized to a core facility or performed on-site. Some tests detect the expression of altered or abnormally expressed subcellular material (proteins, DNA, etc.) in urothelial neoplasms, which are found in tumor cells and/or in the urine specimen when the proteins are either excreted or leaked from degenerating tumor cells. Slide-free tests may also be developed into point-of-care tests, meaning that the result may be available to the urologist but not to the cytopathologist. Since these proteins are often disassociated from the tumor cells that produce them, such tests may have a positive result even if tumor cells are absent in the tested specimen. Here we review critical concepts as well as several ancillary tests that have been developed for urinary tract specimens.


Assuntos
Carcinoma de Células de Transição/diagnóstico , Citodiagnóstico/métodos , Neoplasias da Bexiga Urinária/diagnóstico , Urotélio/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/urina , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/metabolismo , Análise Mutacional de DNA/métodos , Humanos , Hibridização in Situ Fluorescente/métodos , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Sistema Urinário/metabolismo , Sistema Urinário/patologia , Urotélio/metabolismo
2.
Int J Cancer ; 146(1): 281-294, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31286493

RESUMO

DNA/RNA-based classification of bladder cancer (BC) supports the existence of multiple molecular subtypes, while investigations at the protein level are scarce. Here, we aimed to investigate if Nonmuscle Invasive Bladder Cancer (NMIBC) can be stratified to biologically meaningful groups based on the proteome. Tissue specimens from 117 patients at primary diagnosis (98 with NMIBC and 19 with MIBC), were processed for high-resolution proteomics analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The proteomics output was subjected to unsupervised consensus clustering, principal component analysis (PCA) and investigation of subtype-specific features, pathways, and gene sets. NMIBC patients were optimally stratified to three NMIBC proteomic subtypes (NPS), differing in size, clinicopathologic and molecular backgrounds: NPS1 (mostly high stage/grade/risk samples) was the smallest in size (17/98) and overexpressed proteins reflective of an immune/inflammatory phenotype, involved in cell proliferation, unfolded protein response and DNA damage response, whereas NPS2 (mixed stage/grade/risk composition) presented with an infiltrated/mesenchymal profile. NPS3 was rich in luminal/differentiation markers, in line with its pathological composition (mostly low stage/grade/risk samples). PCA revealed a close proximity of NPS1 and conversely, remoteness of NPS3 to the proteome of MIBC. Proteins distinguishing these two extreme subtypes were also found to consistently differ at the mRNA levels between high and low-risk subtypes of the UROMOL and LUND cohorts. Collectively, our study identifies three proteomic NMIBC subtypes and following a cross-omics validation in two independent cohorts, shortlists molecular features meriting further investigation for their biomarker or potentially therapeutic value.


Assuntos
Proteoma/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Cromatografia Líquida/métodos , Progressão da Doença , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Estimativa de Kaplan-Meier , Masculino , Fenótipo , Prognóstico , Proteômica/métodos , RNA Mensageiro/metabolismo , Espectrometria de Massas em Tandem/métodos , Neoplasias da Bexiga Urinária/patologia
3.
Anticancer Res ; 39(12): 6555-6565, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810921

RESUMO

BACKGROUND/AIM: Honokiol is a biphenolic component of the bark of Magnolia, and has been shown to exert several activities, including anti-depressant, anti-emetic, anti-oxidative, anti-thrombotic, anti-angiogenesis, anti-anxiolytic, anti-inflammatory and anti-tumor effects. MATERIALS AND METHODS: The anti-tumor activities of honokiol and its synergistic effect with 5-fluorouracil (5-FU) in human urothelial cell carcinoma (UCC) cells were investigated. RESULTS: Honokiol significantly suppressed the proliferation of UCC cells in a dose- and time-dependent manner. Moreover, honokiol inhibited the tumorigenesis of UCC cells in vitro. In addition, honokiol induced cell cycle arrest at G0/G1 phase and caused apoptosis of UCC cells through the intrinsic pathway. Importantly, we demonstrated that honokiol potentiated the cytotoxic effect of 5-FU, and displayed a synergistic effect with 5-FU in UCC cells. CONCLUSION: Honokiol causes growth inhibition, tumorigenesis suppression, cell cycle arrest, apoptosis, and importantly has a synergistic effect with 5-FU in human UCC cells. Therefore, this agent displays a therapeutic potential for treating human UCC.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Compostos de Bifenilo/farmacologia , Fluoruracila/farmacologia , Lignanas/farmacologia , Neoplasias da Bexiga Urinária/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico
4.
J Cancer Res Clin Oncol ; 145(12): 3075-3087, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31595333

RESUMO

PURPOSE: Bladder cancer represents a major cause of malignancy-related morbidity and the most expensive per-patient-to-treat cancer, due to the lifelong surveillance of the patients. Accurate disease prognosis is essential in establishing personalized treatment decisions; yet optimum tools for precise risk stratification remain a competing task. In the present study, we have performed the complete evaluation of TP63 clinical significance in improving disease prognosis. METHODS: The levels of ΔNp63 and TAp63 transcripts of TP63 were quantified in 342 bladder tissue specimens of our screening cohort (n = 182). Hedegaard et al. (Cancer Cell 30:27-42. doi:10.1016/j.ccell.2016.05.004, 2016) (n = 476) and TCGA provisional (n = 413) were used as validation cohorts for NMIBC and MIBC, respectively. Survival analysis was performed using recurrence and progression for NMIBC or mortality for MIBC as endpoint events. Bootstrap analysis was performed for internal validation, while decision curve analysis was used for the evaluation of the clinical net benefit on disease prognosis. RESULTS: ΔNp63 was significantly expressed in bladder tissues, and was found to be over-expressed in bladder tumors. Interestingly, reduced ΔNp63 levels were correlated with muscle-invasive disease, high-grade tumors and high-EORTC-risk NMIBC patients. Moreover, ΔNp63 loss was independently associated with higher risk for NMIBC relapse (HR = 2.730; p = 0.007) and progression (HR = 7.757; p = 0.016). Hedegaard et al. and TCGA validation cohorts confirmed our findings. Finally, multivariate models combining ΔΝp63 loss with established prognostic markers led to a superior clinical benefit for NMIBC prognosis and risk stratification. CONCLUSIONS: ΔΝp63 loss is associated with adverse outcome of NMIBC resulting in superior prediction of NMIBC early relapse and progression.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Recidiva Local de Neoplasia/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Doença Crônica , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Recidiva , Neoplasias da Bexiga Urinária/patologia
5.
Nat Commun ; 10(1): 4349, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554791

RESUMO

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFß receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFß signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFß receptor stabilisation. This upregulation of the TGFß pathway by HGF leads to TGFß-mediated EMT and invasion. In vivo we show that TGFß receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFß and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-met/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Neoplasias da Bexiga Urinária/genética , Animais , Benzamidas/farmacologia , Linhagem Celular Tumoral , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
Vet Microbiol ; 236: 108396, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31500722

RESUMO

Autophagy is a powerful tool that host cells use to defend against viral infection. Mitophagy, the selective autophagic removal of dysfunctional mitochondria was upregulated in urothelial cancer cells harbouring bovine papillomavirus (BPV) infection, as detected by the expression of BPV E5 protein, the major oncoprotein of bovine Deltapapillomavirus genus. HIF-1α-induced mitophagy receptors, BNIP3 and BNIP3L/Nix, were found to be overexpressed in these cells. The BNIP3 and BNIP3L/Nix receptors were amplified, and amplicon sequencing showed homology between bovine BNPI3 and BNIP3L/Nix sequences deposited in GenBank (accession number: NM_001076366.1 and NM_001034614.2, respectively). The transcripts and protein levels of BNIP3 and BNIP3L/Nix were significantly overexpressed in hypoxic neoplastic cells relative to healthy, non-neoplastic cells. BNIP3 and BNIP3L/Nix interacted with the LC3 protein, a marker of autophagosome (mitophagosome) membrane, ERAS, a small GTPase, and p62, known to be a specific autophagy receptor protein, that plays a role in mitochondrial priming for mitophagy and subsequent elimination. ERAS also interacted with the BPV E5 oncoprotein at mitochondrial level. Furthermore, in anti-Bag3 mitochondrial immunoprecipitates, a complex composed of the Hsc70/Hsp70 chaperone, CHIP co-chaperone, Synpo2, ERAS, LC3, p62, BNPI3, and BNIP3L/Nix was also detected. Bag3 may play a role in mitophagosome formation together with the Synpo2 protein and may be involved in the degradation of Hsc70/Hsp70-bound CHIP-ubiquitinated cargo, in association with its chaperone. ERAS may be involved in mitophagosome maturation via the PI3K signalling pathway. Ultrastructural findings revealed the presence of mitochondria exhibiting severe fragmentation and loss of cristae, as well as numerous mitochondria-containing autophagosomes.


Assuntos
Papillomavirus Bovino 1 , Papillomavirus Bovino 4 , Doenças dos Bovinos/virologia , Infecções por Papillomavirus/veterinária , Proteínas Proto-Oncogênicas/metabolismo , Urotélio/citologia , Animais , Bovinos , Doenças dos Bovinos/patologia , Masculino , Proteínas de Membrana , Proteína Oncogênica p21(ras)/genética , Proteína Oncogênica p21(ras)/metabolismo , Proteínas Oncogênicas Virais , Infecções por Papillomavirus/virologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/ultraestrutura , Neoplasias da Bexiga Urinária/veterinária , Neoplasias da Bexiga Urinária/virologia , Urotélio/metabolismo
7.
Life Sci ; 235: 116832, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31491455

RESUMO

AIMS: Delineates the role of TIS111D in bladder cancer. MATERIALS AND METHODS: The expression of TIS111D in bladder cancer and adjacent tissues was assessed by immunohistochemistry, Western blot and real-time PCR. Western blot and real-time PCR were used to analyse the expression of TIS111D in HT1197, T24, 5637 and TCCSUP cells. After TIS111D was silenced in T24, 5637 and TCCSUP cells, MTT and Transwell assays were used to detect the effects of TIS111D on proliferation and migration. Western blot and real-time PCR were used to detect the regulatory effect of downregulation of TIS111D on N-cad and E-cad. In vivo experiments confirmed the role of TIS111D in the growth and migration of bladder cancer and determined whether the role of TIS111D in bladder cancer is related to its regulation of N-cad and E-cad. KEY FINDINGS: The expression of TIS11D was higher in tumour tissues and bladder cancer cells. Si-TIS111D could inhibit the growth and migration of bladder cancer cells, while TIS111D could regulate the expression of E-cad and N-cad to regulate epithelial-mesenchymal transition (EMT). We also demonstrated that TIS111D could promote the growth and migration of bladder cancer in vivo by regulating EMT. SIGNIFICANCE: TIS111D may participate in the regulation of bladder cancer progression by regulating EMT.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Neoplasias da Bexiga Urinária/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Regulação para Baixo , Humanos , RNA Interferente Pequeno/farmacologia , Fator de Transcrição TFIIIB
8.
Molecules ; 24(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398899

RESUMO

Nobiletin (NOB) is a polymethoxylated flavonoid isolated from citrus fruit peel that has been shown to possess anti-tumor, antithrombotic, antifungal, anti-inflammatory and anti-atherosclerotic activities. The main purpose of this study was to explore the potential of using NOB to induce apoptosis in human bladder cancer cells and study the underlying mechanism. Using an MTT assay, agarose gel electrophoresis, a wound-healing assay, flow cytometry, and western blot analysis, this study investigated the signaling pathways involved in NOB-induced apoptosis in BFTC human bladder cancer cells. Our results showed that NOB at concentrations of 60, 80, and 100 µM inhibited cell growth by 42%, 62%, and 80%, respectively. Cells treated with 60 µM NOB demonstrated increased DNA fragmentation, and flow cytometry analysis confirmed that the treatment caused late apoptotic cell death. Western blot analysis showed that mitochondrial dysfunction occurred in NOB-treated BFTC cells, leading to cytochrome C release into cytosol, activation of pro-apoptotic proteins (caspase-3, caspase-9, Bad, and Bax), and inhibition of anti-apoptotic proteins (Mcl-1, Bcl-xl, and Bcl-2). NOB-induced apoptosis was also mediated by regulating endoplasmic reticulum stress via the PERK/elF2α/ATF4/CHOP pathway, and downregulating the PI3K/AKT/mTOR pathway. Our results suggested that the cytotoxic and apoptotic effects of NOB on bladder cancer cells are associated with endoplasmic reticulum stress and mitochondrial dysfunction.


Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Flavonas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/metabolismo , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
9.
Eur J Pharm Biopharm ; 143: 24-34, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419584

RESUMO

Low permeability of the urinary bladder epithelium, poor retention of the chemotherapeutic agents due to dilution and periodic urine voiding as well as intermittent catheterisations are the major limitations of intravesical drug delivery used in the treatment of bladder cancer. In this work, maleimide-functionalised poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG-Mal) nanoparticles were developed. Their physicochemical characteristics, including morphology, architecture and molecular parameters have been investigated by means of dynamic light scattering, transmission electron microscopy and small-angle neutron scattering techniques. It was established that the size of nanoparticles was dependent on the solvent used in their preparation and molecular weight of PEG, for example, 105 ±â€¯1 nm and 68 ±â€¯1 nm particles were formed from PLGA20K-PEG5K in dimethyl sulfoxide and acetone, respectively. PLGA-PEG-Mal nanoparticles were explored as mucoadhesive formulations for drug delivery to the urinary bladder. The retention of fluorescein-loaded nanoparticles on freshly excised lamb bladder mucosa in vitro was evaluated and assessed using a flow-through fluorescence technique and Wash Out50 (WO50) quantitative method. PLGA-PEG-Mal nanoparticles (NPs) exhibited greater retention on urinary bladder mucosa (WO50 = 15 mL) compared to maleimide-free NPs (WO50 = 5 mL). The assessment of the biocompatibility of PEG-Mal using the slug mucosal irritation test revealed that these materials are non-irritant to mucosal surfaces.


Assuntos
Portadores de Fármacos/química , Maleimidas/administração & dosagem , Maleimidas/química , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Animais , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Peso Molecular , Membrana Mucosa/metabolismo , Tamanho da Partícula , Ovinos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
10.
Scand J Immunol ; 90(6): e12818, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31448424

RESUMO

Bladder cancer is one of the leading causes of death worldwide. The main immune mechanisms which lead to bladder cancer development or treatment outcomes have yet to be elucidated. Toll-like receptors (TLRs) play key roles against cancer. TLRs are expressed both on immune cells and on tumour cells and drive immune responses in progression as well as treatment of cancer. Identification of signalling pathways via TLRs could revolutionize further improvement of therapeutic strategies against cancers in the future. According to the recent studies, TLRs agonists are effective immunostimulants and have important role in induction of immune responses with immunotherapeutic potential against several diseases including cancer. They play an important role in the bladder urothelium as a part of immune defence against uropathogens. On the other hand, decreased TLRs expression was found in bladder tumours, particularly in non-muscle-invasive ones. Bacillus Calmette-Guerin (BCG) (agonist of TLR2 and TLR4) is approved by US FDA for immunotherapy of bladder cancer. Despite high efficiency, immunotherapy with BCG may cause toxicity and adverse effects. Nowadays, in vitro and in vivo studies have been conducted to find alternative options for non-responder patients. Studies on TLR agonists for bladder cancer treatment have shown promising results. In this review, we discuss recent data about mechanisms played by TLRs in bladder cancer developments as well as therapeutic application of TLR agonists in cancer treatment.


Assuntos
Receptores Toll-Like/metabolismo , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/metabolismo , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Fenômenos Imunogenéticos , Imunoterapia/métodos , Ligantes , Terapia de Alvo Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo Genético , Transdução de Sinais , Receptores Toll-Like/agonistas , Receptores Toll-Like/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia
11.
Chem Biodivers ; 16(10): e1900334, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31448497

RESUMO

Cernumidine (CER) is a guanidinic alkaloid isolated from Solanum cernuum leaves. In this work, we investigated the cytotoxicity, chemosensitizing effect of cernumidine to cisplatin (cDDP) and the possible mechanism of action of the combination on bladder cancer cells. Cernumidine showed cytotoxicity and could sensitize bladder cancer cells to cisplatin. The combination of CER+cDDP inhibited cell migration on T24 cells. CER+cDDP down-regulated MMP-2/9 and p-ERK1/2, while it increased EGFR activity corroborating the observed cell migration inhibition. Down-regulation of Bcl-2 and up-regulation pro-apoptotic Bax and further depletion of the mitochondrial membrane potential (ΔΨm) indicates that mitochondria play a central role in the combination treatment inducing the mitochondrial signaling pathway of apoptosis in T24 cells. Our data showed that the alkaloid cernumidine is worthy of further studies as a chemosensitizing agent to be used in complementary chemotherapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ácidos Cafeicos/farmacologia , Guanidinas/farmacologia , Solanum/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Ácidos Cafeicos/química , Ácidos Cafeicos/isolamento & purificação , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Guanidinas/química , Guanidinas/isolamento & purificação , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microscopia de Fluorescência , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Folhas de Planta/química , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
12.
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
13.
J Cancer Res Clin Oncol ; 145(9): 2261-2271, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31367836

RESUMO

PURPOSE: To investigate the role of sonic hedgehog (Shh) signaling and epithelial-mesenchymal transition (EMT) in bladder cancer progression and invasion. METHODS: We cultured three bladder cancer cell lines, muscle-invasive T24 and 5637, and non-muscle-invasive KK47, in the presence of a recombinant-Shh (r-Shh) protein or cyclopamine, a Shh signaling inhibitor, to investigate proliferation and expression of EMT markers. Wound-healing assays and transwell assay were performed to evaluate cell invasion and migration. Mice were then inoculated with bladder cancer cells and treated with cyclopamine. Mouse tumor samples were stained for Shh signaling and EMT markers. RESULTS: R-Shh protein enhanced cell proliferation, whereas cyclopamine significantly suppressed cell proliferation, especially in invasive cancer (5637 and T24) (p < 0.05). R-Shh protein promoted EMT, suppressed E-cadherin and enhanced N-cadherin and vimentin and Gli1, an Shh downstream molecule, while cyclopamine blocked EMT, especially in 5637 and T24. Cyclopamine also inhibited cell invasion and migration in vitro. In the animal study, intraperitoneal injection of cyclopamine significantly suppressed tumor growth in 5637 and T24 in mice (p = 0.01 and p = 0.004, respectively) and slightly suppressing KK47 tumor growth (p = 0.298). Significant cyclopamine-induced suppression of Gli1 in 5637 and T24 mouse tumors (both p = 0.03) was seen, suggesting that muscle-invasive bladder cancer may be more dependent on Shh signaling than non-muscle-invasive bladder cancer. CONCLUSIONS: Shh signaling and EMT were especially enhanced in muscle-invasive bladder cancer progression and invasion, and suppressed by the inhibition of Shh signaling.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Proteínas Hedgehog/fisiologia , Neoplasias Musculares/secundário , Neoplasias da Bexiga Urinária/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Musculares/metabolismo , Invasividade Neoplásica , Transdução de Sinais/fisiologia , Neoplasias da Bexiga Urinária/metabolismo
14.
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
15.
Int J Mol Sci ; 20(15)2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31387245

RESUMO

Licochalcone A (LCA) is a chalcone that is predominantly found in the root of Glycyrrhiza species, which is widely used as an herbal medicine. Although previous studies have reported that LCA has a wide range of pharmacological effects, evidence for the underlying molecular mechanism of its anti-cancer efficacy is still lacking. In this study, we investigated the anti-proliferative effect of LCA on human bladder cancer cells, and found that LCA induced cell cycle arrest at G2/M phase and apoptotic cell death. Our data showed that LCA inhibited the expression of cyclin A, cyclin B1, and Wee1, but increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1, and increased p21 was bound to Cdc2 and Cdk2. LCA activated caspase-8 and -9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. Additionally, LCA increased the Bax/Bcl-2 ratio, and reduced the integrity of mitochondria, which contributed to the discharge of cytochrome c from the mitochondria to the cytoplasm. Moreover, LCA enhanced the intracellular levels of reactive oxygen species (ROS); however, the interruption of ROS generation using ROS scavenger led to escape from LCA-mediated G2/M arrest and apoptosis. Collectively, the present data indicate that LCA can inhibit the proliferation of human bladder cancer cells by inducing ROS-dependent G2/M phase arrest and apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Chalconas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Biomarcadores , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo
16.
Indian J Cancer ; 56(3): 254-260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389390

RESUMO

BACKGROUND: Non-urothelial bladder tumors (NUBTs) are uncommon accounting for approximately 10% of the total urinary bladder tumors while 90% are urothelial in origin. There are very limited comprehensive studies on NUBTs. AIMS AND OBJECTIVES: The objectives of the study were to analyze the clinicopathological and immunohistochemical features of NUBTs. MATERIALS AND METHODS: This is a retrospective study of NUBTs diagnosed over a period of 9 years. Patients' files were retrieved from the archives. Gross and microscopic features were recorded. Simple percentage and frequencies were used to interpret the data. RESULTS: A total 16 cases (10.8% of all bladder tumors) of NUBT were found. Patients' ages ranged from 19 to 87 years with a male: female ratio of 4.3:1. The most common presenting symptom was gross hematuria (81.2%), and the most common location was posterolateral bladder wall. Muscle invasion was seen in 81.2% of cases, and large areas of necrosis were observed in 62.5%. There were two cases of squamous cell carcinoma, five cases each of adenocarcinoma (four secondary and one urachal) and mesenchymal tumors (four malignant and one benign), two cases of amyloid, and one case each of plasmacytomas and paraganglioma. Large areas of necrosis and muscle invasion were noted in high-grade and advanced staged tumors. In all, 43.7% had poor survival. CONCLUSION: NUBTs present with similar clinicoradiological findings; however, their histological features along with immunohistochemistry help in the definite diagnosis. One should be aware of these tumors as they frequently present diagnostic and therapeutic challenge. Most of these neoplasms present at an advanced stage. Large or multicentric randomized controlled studies are needed to know the exact behavior and prognosis of these tumors.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Imuno-Histoquímica/métodos , Neoplasias da Bexiga Urinária/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/cirurgia , Adulto Jovem
17.
Int J Mol Sci ; 20(15)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31382543

RESUMO

This Special Issue of International Journal of Molecular Sciences (IJMS) covers one of the most intriguing and emerging fields in terms of molecular oncology and uro-oncologic research efforts over the recent years, namely urothelial carcinoma of the bladder (UCB), as well as urothelial carcinoma of the upper urinary tract (UTUC). A total of 8 articles published in this Special Issue highlight the current progress in molecular oncology and cancer genetics in UCB, including a wide range of research topics, such as FGFR-inhibitors, sarcopenia in UCB, molecular predictors of response following neoadjuvant chemotherapy, exercise cardiac training impacts in the murine UCB model, Obatoclax, tropomyosins as potential biomarkers, immunotherapeutic approaches, as well as a transcriptional analysis of immunohistochemically defined UCB-subgroups. Find a brief summary of the respective articles below.


Assuntos
Neoplasias da Bexiga Urinária/patologia , Bexiga Urinária/patologia , Urotélio/patologia , Animais , Exercício , Humanos , Imunoterapia , Terapia Neoadjuvante , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/terapia , Urotélio/efeitos dos fármacos , Urotélio/metabolismo
18.
BMC Urol ; 19(1): 69, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340801

RESUMO

BACKGROUND: The expression level of ribonucleotide reductase subunit M1 (RRM1) is closely related to the effect of gemcitabine-based therapy in advanced bladder cancer. However, the value of RRM1 expression in predicting progression-free survival in non-muscle-invasive bladder cancer (NMIBC) patients treated with intravesical gemcitabine chemotherapy has not been elucidated. METHODS: This study randomly assigned 162 patients to either the RRM1-known group or the unknown group. We collected cancer tissues from 81 patients to evaluate the mRNA expression of RRM1 by using liquid chip technology. All patients were diagnosed and then treated with intravesical gemcitabine monotherapy immediately after transurethral resection of the bladder tumour (TURBT). RESULTS: RRM1 expression was high in 21% (17/81) of patients. The RRM1 mRNA level was not correlated with sex, age, weight, performance status, or CUA/EAU risk (p > 0.05). Progression-free survival (PFS) was significantly longer for patients with low RRM1 expression than for patients with high and unknown RRM1 expression (p = 0.009). Additionally, the 1- and 2-year relapse rates also differed according to RRM1 expression level. The 1-year relapse rates for RRM1-low, RRM1-high and RRM1-unknown patients were 0, 17.7 and 6.2% (p = 0.009), while the 2-year relapse rates for these groups were 3.1, 29.4, and 11.1% (p = 0.005), respectively. CONCLUSIONS: This preliminary study showed that low RRM1 expression was associated with longer progression-free survival and lower 1-year/2-year relapse rates in NMIBC patients treated with intravesical gemcitabine monotherapy, despite the need for further verification with large sample sizes and considering more mixed factors and biases.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/biossíntese , Desoxicitidina/análogos & derivados , Ribonucleosídeo Difosfato Redutase/biossíntese , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Administração Intravesical , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/diagnóstico , Valor Preditivo dos Testes , Distribuição Aleatória , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Neoplasias da Bexiga Urinária/diagnóstico
19.
Virchows Arch ; 475(5): 599-608, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31267201

RESUMO

Programmed death-ligand 1 (PD-L1) expression on tumor cells (TC) or tumor-infiltrating immune cells (IC) correlated in several studies with PD-L1/programmed death-1 (PD-1) checkpoint inhibitor efficacy. Since June 2018, a positive PD-L1 status is required for atezolizumab or pembrolizumab treatment of patients with advanced or metastasized urothelial bladder cancer, who are ineligible for cisplatin-containing therapy. We examined technical comparability and inter-reader agreement of four clinically developed PD-L1 assays in locally advanced disease. Archived, formalin-fixed, paraffin-embedded sections from 30 patients (73.3% cystectomies, 26.7% transurethral resections) were stained by PD-L1 immunohistochemistry using VENTANA SP142, VENTANA SP263, DAKO 22C3, and DAKO 28-8 at two sites per manufacturers' protocols and scored blinded at five sites for PD-L1 expression on IC (% per tumor area) and TC (%). Small, non-significant inter-assay differences were observed for IC. For TC, SP142 showed significantly lower staining percentages. Pairwise comparisons revealed - 0.3 to 1.6% differences in adjusted means between assays for IC, and for TC, - 10.5 to - 7.8% (SP142 versus others) and - 1.9 to 2.7% (other comparisons). Inter-reader and inter-assay agreement was moderate to high for both IC and TC. Allocation to binary cutoffs (1%, 5%, 10%) showed substantial to high Kappa agreement scores (0.440-0.923) for IC and TC between assays for each reader. This first multicenter study, with five independent readers blinded with respect to the assay used, suggests that all four currently clinically relevant assays are analytically similar for evaluation of PD-L1-stained IC and three (SP263, 22C3, and 28-8) for PD-L1-stained TC. Inter-observer agreement for trained readers in scoring of both IC and TC positivity was generally high.


Assuntos
Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células de Transição/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral , Variações Dependentes do Observador , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia
20.
Int J Oncol ; 55(2): 359-370, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268162

RESUMO

Sry­Related HMG­BOX­4 (SOX4) is a developmental transcription factor that is overexpressed in as many as 23% of bladder cancer patients; however, the role of SOX4 in bladder cancer tumorigenesis is not yet well understood. Given the many roles of SOX4 in embryonic development and the context­dependent regulation of gene expression, in this study, we sought to determine the role of SOX4 in bladder cancer and to identify SOX4­regulated genes that may contribute to tumorigenesis. For this purpose, we employed a CRISPR interference (CRISPRi) method to transcriptionally repress SOX4 expression in T24 bladder cancer cell lines, 'rescued' these cell lines with the lentiviral­mediated expression of SOX4, and performed whole genome expression profiling. The cells in which SOX4 was knocked down (T24­SOX4­KD) exhibited decreased invasive capabilities, but no changes in migration or proliferation, whereas rescue experiments with SOX4 lentiviral vector restored the invasive phenotype. Gene expression profiling revealed 173 high confidence SOX4­regulated genes, including WNT5a as a potential target of repression by SOX4. Treatment of the T24­SOX4­KD cells with a WNT5a antagonist restored the invasive phenotype observed in the T24­scramble control cells and the SOX4 lentiviral­rescued cells. High WNT5a expression was associated with a decreased invasion and WNT5a expression inversely correlated with SOX4 expression, suggesting that SOX4 can negatively regulate WNT5a levels either directly or indirectly and that WNT5a likely plays a protective role against invasion in bladder cancer cells.


Assuntos
Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOXC/metabolismo , Neoplasias da Bexiga Urinária/patologia , Proteína Wnt-5a/metabolismo , Apoptose , Humanos , Invasividade Neoplásica , Prognóstico , RNA Interferente Pequeno/genética , Fatores de Transcrição SOXC/antagonistas & inibidores , Fatores de Transcrição SOXC/genética , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Proteína Wnt-5a/genética
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