RESUMEN
The tumor suppressor gene BRCA1 associated protein-1 (BAP1) is frequently mutated in renal cell carcinoma (RCC). BAP1 loss-of-function mutations are associated with poor survival outcomes. However, personalized therapy for BAP1-mutated RCC is currently not available. Previously, we found that BAP1 loss renders RCC cells more sensitive to bromodomain and extra-terminal (BET) inhibitors, as demonstrated in both cell culture and xenografted nude mice models. Here, we demonstrate that BAP1 loss in murine RCC cells enhances sensitivity to BET inhibitors in ectopic and orthotopic allograft models. While BAP1 deletion suppresses RCC cell survival in vitro, it does not impede tumor growth in immunocompetent murine models. Thus, the effect of BAP1 loss on the interactions between tumor cells and host microenvironment plays a predominant role in RCC growth, highlighting the importance of utilizing immunocompetent animal models to assess the efficacy of potential anticancer therapies. Mechanistically, BAP1 deletion compromises DNA repair capacity, rendering RCC cells more vulnerable to DNA damage induced by BET inhibitors. Our results indicate that BET inhibitors show promise as targeted therapy for BAP1-deficient RCC.
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Uveal melanoma (UM) is the most common intraocular cancer in adults. UMs are usually initiated by a mutation in GNAQ or GNA11 (encoding Gq or G11, respectively), unlike cutaneous melanomas (CMs), which usually carry a BRAF or NRAS mutation. Currently, there are no clinically effective targeted therapies for UM carrying Gq/11 mutations. Here, we identified a causal link between Gq activating mutations and hypersensitivity to bromodomain and extra-terminal (BET) inhibitors. BET inhibitors transcriptionally repress YAP via BRD4 regardless of Gq mutation status, independently of Hippo core components LATS1/2. In contrast, YAP/TAZ downregulation reduces BRD4 transcription exclusively in Gq-mutant cells and LATS1/2 double knockout cells, both of which are featured by constitutively active YAP/TAZ. The transcriptional interdependency between BRD4 and YAP identified in Gq-mutated cells is responsible for the preferential inhibitory effect of BET inhibitors on the growth and dissemination of Gq-mutated UM cells compared to BRAF-mutated CM cells in both culture cells and animal models. Our findings suggest BRD4 as a viable therapeutic target for Gq-driven UMs that are addicted to unrestrained YAP function.
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Melanoma , Proteínas Nucleares , Animales , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/genética , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas B-raf/genética , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias de la ÚveaRESUMEN
The tumor suppressor gene BAP1 encodes a widely expressed deubiquitinase for histone H2A. Both hereditary and acquired mutations are associated with multiple cancer types, including cutaneous melanoma (CM), uveal melanoma (UM), and clear cell renal cell carcinoma (ccRCC). However, there is no personalized therapy for BAP1-mutant cancers. Here, we describe an epigenetic drug library screening to identify small molecules that exert selective cytotoxicity against BAP1 knockout CM cells over their isogenic parental cells. Hit characterization reveals that BAP1 loss renders cells more vulnerable to bromodomain and extraterminal (BET) inhibitor-induced transcriptional alterations, G1/G0 cell cycle arrest and apoptosis. The association of BAP1 loss with sensitivity to BET inhibitors is observed in multiple BAP1-deficient cancer cell lines generated by gene editing or derived from patient tumors as well as immunodeficient xenograft and immunocompetent allograft murine models. We demonstrate that BAP1 deubiquitinase activity reduces sensitivity to BET inhibitors. Concordantly, ectopic expression of RING1A or RING1B (H2AK119 E3 ubiquitin ligases) enhances sensitivity to BET inhibitors. The mechanistic study shows that the BET inhibitor OTX015 exerts a more potent suppressive effect on the transcription of various proliferation-related genes, especially MYC, in BAP1 knockout cells than in their isogenic parental cells, primarily by targeting BRD4. Furthermore, ectopic expression of Myc rescues the BET inhibitor-sensitizing effect induced by BAP1 loss. Our study reveals new approaches to specifically suppress BAP1-deficient cancers, including CM, UM, and ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Melanoma , Neoplasias Cutáneas , Animales , Carcinoma de Células Renales/tratamiento farmacológico , Proteínas de Ciclo Celular , Humanos , Neoplasias Renales/genética , Melanoma/genética , Ratones , Proteínas Nucleares , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Neoplasias de la Úvea , Melanoma Cutáneo MalignoRESUMEN
Rapalogs (everolimus and temsirolimus) are allosteric mTORC1 inhibitors and approved agents for advanced clear cell renal cell carcinoma (ccRCC), although only a subset of patients derive clinical benefit. Progress in genomic characterization has made it possible to generate comprehensive profiles of genetic alterations in ccRCC; however, the correlations between recurrent somatic mutations and rapalog efficacy remain unclear. Here, we demonstrate by using multiple patient-derived ccRCC cell lines that compared to PTEN-proficient cells, PTEN-deficient cells exhibit hypersensitivity to rapalogs. Rapalogs inhibit cell proliferation by inducing G0/G1 arrest without inducing apoptosis in PTEN-deficient ccRCC cell lines. Using isogenic cell lines generated by CRISPR/Cas9, we validate the correlation between PTEN loss and rapalog hypersensitivity. In contrast, deletion of VHL or chromatin-modifying genes (PBRM1, SETD2, BAP1, or KDM5C) fails to influence the cellular response to rapalogs. Our mechanistic study shows that ectopic expression of an activating mTOR mutant (C1483F) antagonizes PTEN-induced cell growth inhibition, while introduction of a resistant mTOR mutant (A2034V) enables PTEN-deficient ccRCC cells to escape the growth inhibitory effect of rapalogs, suggesting that PTEN loss generates vulnerability to mTOR inhibition. PTEN-deficient ccRCC cells are more sensitive to the inhibitory effects of temsirolimus on cell migration and tumor growth in zebrafish and xenograft mice, respectively. Of note, PTEN protein loss as detected by immunohistochemistry is much more frequent than mutations in the PTEN gene in ccRCC patients. Our study suggests that PTEN loss correlates with rapalog sensitivity and could be used as a marker for ccRCC patient selection for rapalog therapy.
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Carcinoma de Células Renales , Neoplasias Renales , Animales , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/patología , Inhibidores mTOR , Ratones , Mutación , Fosfohidrolasa PTEN/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Supresoras de Tumor/genética , Pez Cebra/metabolismo , Proteínas de Pez CebraRESUMEN
Previous studies identified an association of low-density lipoprotein (LDL) levels and LDL receptor (LDLR) with renal cell carcinoma (RCC) development. This study investigated the expression and roles of LDLR in RCC. LDLR expression was examined in clear cell RCC (ccRCC) and adjacent normal kidney tissues, and its clinicopathological significance was analyzed. The role of LDLR in RCC cell proliferation, cell cycle, and invasion were assessed in RCC cells with LDLR stable knockdown. LDLR expression was higher in ccRCC tissues than in normal kidney tissues and increased with RCC progression. LDLR knockdown in RCC cells inhibited cell growth, migration and invasion, and induced G1/S cell cycle arrest. We identified an interaction between LDLR and EGFR, and EGFR signaling protein expression was reduced after LDLR knockdown. Our findings reveal that LDLR plays an important role in RCC carcinogenesis, suggesting that LDL and LDLR might be potential targets for therapeutic intervention in RCC.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Receptores de LDL/genéticaRESUMEN
BACKGROUND There are few studies that address how to quickly locate the renal vein after processing the renal artery during retroperitoneal laparoscopic radical nephrectomy (RLRN) for renal cell carcinoma (RCC). This study aimed to evaluate the feasibility of an easy and effective method to locate the renal vein in RLRN. MATERIAL AND METHODS Between September 2016 and October 2017, a total of 44 consecutive cases of RLRN were performed. All the surgeries used the proposed study method to locate the renal vein, in which surgeons located the renal artery following the medial arcuate ligament on the posterior abdominal wall, then the surgeon directly searched for the renal vein caudally relative to renal artery when performing left nephrectomy, but cranially when performing right nephrectomy. RESULTS Among the 44 enrolled RLRN patients, there were 28 left nephrectomies and 16 right nephrectomies. We found the renal vein in most cases successfully by our proposed method. The renal vein was located caudally relative to the renal artery in 27 cases of the left kidney (96.4%), and was located cranially in 14 cases of the right kidney (87.5%). The mean operative time was 135.0±27.8 minutes. No intraoperative complications occurred. Postoperative complications (fever) developed in 5 patients. Pathological examination revealed: clear cell carcinoma in 34 cases (77.3%), chromophobe renal cell carcinoma (RCC) in 5 cases (11.4%), papillary RCC in 3 cases (6.8%), multilocular cystic RCC in 1 case (2.3%), and oxyphil cell adenoma in 1 case (2.3%). CONCLUSIONS Our proposed method to search for the renal vein might be a safe and feasible procedure to accelerate the process of handling the renal pedicle and of great practical significance in RLRN surgery.
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Laparoscopía/métodos , Nefrectomía/métodos , Adulto , Anciano , Femenino , Humanos , Riñón/patología , Masculino , Persona de Mediana Edad , Tempo Operativo , Complicaciones Posoperatorias/patología , Arteria Renal/patología , Venas Renales/diagnóstico por imagen , Venas Renales/cirugía , Espacio Retroperitoneal/cirugía , Resultado del TratamientoRESUMEN
Recent studies indicate that abnormal levels of low-density lipoprotein (LDL), which is an important component of dyslipidaemia, are associated with alterations to cancer risk, including that of renal cell carcinoma (RCC). Single nucleotide polymorphisms at microRNA-binding sites contribute to cancer susceptibility and progression by affecting the messenger RNA (mRNA) function of target genes. In this case-control study, we examined the frequency of six potentially functional single nucleotide polymorphisms in the LDL receptor gene (LDLR) in 1004 clear cell RCC (ccRCC) patients and 1065 cancer-free subjects. Logistic regression analyses estimated odds ratios (ORs) and 95% confidence intervals (CIs). The association between genetic variants and levels of LDLR mRNA and protein was also evaluated. Compared with the CC genotype, multivariate logistic regression analysis showed that the LDLR rs2738464 variant GG genotype was associated with a significantly decreased ccRCC risk (P = 0.002, OR: 0.605, 95% CI: 0.439-0.833). Further functional experiments showed that the rs2738464 variant G allele affected miR-330 regulation of the LDLR 3'-untranslated region (UTR), increasing LDLR mRNA levels in patient kidney tissues. These findings suggest that LDLR rs2738464 may affect the affinity of miR-330 binding to the LDLR 3'-UTR, thus regulating LDLR expression and contributing to ccRCC risk.
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Carcinoma de Células Renales/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias Renales/genética , Receptores de LDL/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Genotipo , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: To investigate the association between smoking and different prostate cancer (PCa) pathological subtypes incidence in Chinese men. PATIENTS AND METHODS: We prospectively included 1795 patients who underwent prostate biopsies in one tertiary center between March 2013 and April 2016. Clinical data and biopsy outcomes were collected. Logistic regression was used to evaluate the association between cigarette smoking and PCa incidence. RESULTS: A total of 737 men, 480 men and 58 men were diagnosed with PCa, high-grade PCa (HGPCa, grade group ≥ 4 as accepted by the 2014 ISUP) and intraductal carcinoma of the prostate (IDC-P), respectively. Current smokers had a significantly higher risk of HGPCa than never smokers (OR = 1.89, 95%CI: 1.44-2.48). No such association was observed for low-grade disease and cigarette smoking (OR = 0.84, 95%CI: 0.61-1.16). In a sub-analysis, men who had smoked longer than 30 years had a higher risk of HGPCa, compared with men who had smoked fewer than 30 years (OR = 1.50, 95%CI: 1.09-2.06). Current smokers were more likely to develop IDC-P than never smokers (OR = 2.29, 95%CI: 1.14-4.59). CONCLUSION: Among men in this Chinese biopsy cohort, current smoking was associated with highly malignant PCa incidence, such as HGPCa and IDC-P. The duration of smoking may be associated with HGPCa.
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Carcinoma Ductal , Próstata/patología , Neoplasias de la Próstata , Fumar/epidemiología , Anciano , Biopsia/métodos , Biopsia/estadística & datos numéricos , Carcinoma Ductal/epidemiología , Carcinoma Ductal/patología , China/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/patología , Factores de Riesgo , Estadística como AsuntoRESUMEN
Fibroblast growth factor 8b and androgen play important roles in cell proliferation of prostate cancer. We investigated the effects of fibroblast growth factor 8b and androgen on the proliferation of prostate cell lines and the corresponding intracellular mechanisms. It is found that dihydrotestosterone and fibroblast growth factor 8b stimulated Lncap cell mitosis in a concentration-responsive manner, with 30 ng/mL as the most suitable concentration, respectively. Dihydrotestosterone treatment alone did not enhance the expression and phosphorylation level of fibroblast growth factor receptor but significantly enhanced the level of fibroblast growth factor receptor phosphorylation elicited by fibroblast growth factor 8b. Phosphorylations of extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase were stimulated by dihydrotestosterone or fibroblast growth factor 8b. Among these major downstream pathways for mitogen-activated protein kinase, c-Jun NH2-terminal kinase signaling was most significantly enhanced. Protein kinase C phosphorylation was higher than AKT by the combined stimulation of dihydrotestosterone and fibroblast growth factor 8b. The phosphorylation of CDC2 was significantly induced by dihydrotestosterone and fibroblast growth factor 8b synergetically, and Smad underwent the same induction as CDC2. So the promoting effect of fibroblast growth factor 8b on cell cycle might contribute to the G2/M transition. This study indicated that the functional interaction between fibroblast growth factor 8b and androgen was essential for the prostate cancer cell proliferation.
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Proliferación Celular/efectos de los fármacos , Dihidrotestosterona/farmacología , Factor 8 de Crecimiento de Fibroblastos/farmacología , Fase G2/efectos de los fármacos , Neoplasias de la Próstata/patología , Proteína Quinasa CDC2 , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Factor 8 de Crecimiento de Fibroblastos/metabolismo , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Fosforilación/efectos de los fármacos , Proteínas Smad/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
PURPOSE: To test the hypothesis that miR429 expression in renal cancer patients is increased and plays a role in the pathogenesis of the disease. METHODS: Twenty-seven renal cancer patients admitted to our hospital from May 2014 to May 2015 were enrolled as the study group, and 28 non-cancer patients were selected during the same period as the control group. Renal biopsy and serum samples were used to detect miR429 expression levels, and the patient histories were obtained to make relevant associations to clinical outcomes. In addition, the renal cancer cell line SK458 was used for overexpressing or knocking out miR429 in in vitro experiments to observe changes in proliferation and apoptosis rates. RESULTS: The expression levels of miR429 in renal tissues and serum of renal cancer patients were significantly higher compared with control patients (p<0.05). In addition, a correlation was found between the levels of miR429 in the serum of renal cell cancer patients and their clinical outcome after conventional treatment, with patients expressing lower miR429 levels showing better clinical outcomes. Finally, experiments with renal cancer cells revealed that the proliferation of cells overexpressing miR429 was increased and their apoptosis rate was significantly reduced, while the opposite was true in miR429-knockout cells. CONCLUSIONS: It seems that miR429 can inhibit normal apoptosis rates and lead to high proliferation rates. Accordingly, the higher serum miR429 level in renal cancer patients suggests that it plays a role in the pathogenesis of the disease, while the differential miR429 levels according to the patients' clinical outcomes after treatment suggest that miR429 may be useful as a marker for prognosis.
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Carcinoma de Células Renales/genética , MicroARNs/metabolismo , Adulto , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Masculino , PronósticoRESUMEN
OBJECTIVE: To evaluate the correlation between the level of adipocytokines expression in periprostatic adipose tissue and the prostate cancer aggressiveness. PATIENTS AND METHOD: The periprostatic adipose tissues were collected from 30 patients who underwent radical retropubic prostatectomy. The subcutaneous adipose, periprostatic adipose tissues and prostate cancer tissue from the same patient were collected from 10 patients for match research. The expression level of IL-6, Leptin and Adiponectin was detected by immunohistochemistry and by Real-time quantitative PCR in periprostatic adipose tissues. RESULT: There were differences in the positive rates of IL-6, Leptin and Adiponectin expression in the periprostate adipose between prostate cancer and control (P<0.001, P=0.032, 0.003). Nothing but the "IL-6 expression intensity" was seen in difference with the aggressiveness of prostate cancer (P=0.001), and was relevant with the prostate cancer aggressiveness (rs=0.668, P<0.001); The mRNA expression of IL-6 in periprostatic adipose tissues of prostate cancer was higher than that of control (P=0.049), and the mRNA expression of Adiponectin was lower (P<0.0001); IL-6 mRNA expression in periprostate adipose tissue and prostate cancer tissue were higher than that in subcutaneous adipose (P<0.001, P=0.001); IL-6 mRNA expression in periprostate adipose was correlated with that in prostate cancer tissue (r=0.663, p=0.036); Adiponectin mRNA expression in prostate cancer tissue was lower than that in periprostate adipose (P=0.006), and Adiponectin mRNA expression in periprostate adipose was correlated with that in prostate cancer tissue (r=0.707, p=0.022). CONCLUSION: IL-6, Leptin and Adiponectin were expressed in the periprostatic adipose tissues, which constitute the microenvironment of prostate cancer aggressiveness. There might be intimate relationship between periprostate adipose and prostate cancer tissue.
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Adipoquinas/metabolismo , Tejido Adiposo/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Humanos , Interleucina-6/metabolismo , Leptina/metabolismo , Masculino , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is associated with clinical outcomes of various cancers. This study aimed to evaluate whether pretreatment NLR can be used as a prognostic factor in patients with metastatic renal cell carcinoma (mRCC) receiving targeted therapy. METHODS: In this single-center retrospective study, the Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) of 373 mRCC patients receiving targeted therapy. The survival outcomes of patients with high (≥ 2.2) and low (< 2.2) pretreatment NLRs were compared by log-rank test, and Cox proportional hazard regression model was used to compare OS and PFS between groups. RESULTS: The overall median PFS and OS times for all 373 patients were 18.4 and 34.3 months, respectively. Patients with high NLRs had significantly shorter median OS (28.8 vs 410 months, P = 0.005) and PFS (15.4 vs 23.9 months, P = 0.001) than those with low NLRs. After adjusting for confounding variables, each unit increase of NLR was associated with a 40 % increase in mortality (hazard ratio [HR] 1.391; 95 % confidence interval [CI] 1.022-1.894; P = 0.036). High NLR was also an independent predictor of poor PFS (HR 1.544; 95 % CI 1.166-2.045; P = 0.002). CONCLUSION: Pretreatment NLR may be an independent prognostic factor for mRCC patients who are receiving targeted therapy.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/secundario , Neoplasias Renales/patología , Linfocitos/patología , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Neutrófilos/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Humanos , Neoplasias Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Although pretreatment neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), and platelet-lymphocyte ratio (PLR) are reportedly associated with clinical outcomes of many cancers, their roles in patients with bladder cancer (BCa) who undergo radical cystectomy (RC) have not been widely investigated. We analyzed relationships between preoperative NLR, LMR, PLR, and overall survival (OS) in 124 BCa patients undergoing RC. OS curves were drawn using the Kaplan-Meier method and evaluated using the log-rank test. Relationships between OS and potential confounding variables were determined using Cox's proportional hazard regression model. Decreased LMR was associated with shorter OS (P = 0.012); OS in the low PLR group was significantly longer than that in the high PLR group (P = 0.029), and NLR was not significantly associated with oncological outcomes. However, after adjusting for confounding variables, patients in the high-LMR group indicated >30% decreased mortality than the low-LMR group (hazard ratio 0.674; 95% confidence interval 0.412-0.890; P = 0.003), and PLR was not an independent predictor of OS. Our results show that preoperative LMR is a better prognostic factor in BCa patients undergoing RC, compared with NLR and PLR.
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Plaquetas/patología , Linfocitos/patología , Monocitos/patología , Pronóstico , Neoplasias de la Vejiga Urinaria/patología , Anciano , Anciano de 80 o más Años , Cistectomía , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Neutrófilos/patología , Periodo Preoperatorio , Neoplasias de la Vejiga Urinaria/sangre , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
BACKGROUND: Evidence of the association of metabolic syndrome (MetS) with cancer risk is accumulating. However, uncertainties still exist as to the link of MetS with bladder cancer. This study aimed to assess the relationship between MetS and the risk of urothelial carcinoma of the bladder (UC) in a Chinese population. METHODS: We retrospectively analyzed clinicopathological data of 972 newly diagnosed UC patients and 1098 cancer-free controls matched to the cases by age and gender. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression in both unadjusted and adjusted models. RESULTS: MetS was not significantly associated with the overall UC risk (p=0.08). However, a significant association of MetS with UC was observed in female patients (p=0.006). Diabetes mellitus (crude OR 1.339, 95% CI 1.079-1.662, p=0.008; adjusted OR 1.767, 95% CI 1.308-2.386, p<0.001) and hypertriglyceridemia (crude OR 1.245, 95% CI 1.018-1.522, p=0.033; adjusted OR 1.254, 95% CI 1.020-1.542, p=0.032) were significantly associated with UC risk. As the number of MetS components increased, the UC risk was elevated. Having three or more (versus zero) components of MetS was significantly related to risk of overall UC (OR 1.315; 95% CI 1.006-1.719; p=0.045) and non-muscle invasive bladder cancer (OR 1.354; 95% CI 1.019-1.798; p=0.037). CONCLUSIONS: The present study indicated a marginal association between MetS and UC risk, and a significant association with UC risk in female patients. The results need to be evaluated in large-scale prospective cohorts.
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Síndrome Metabólico/complicaciones , Neoplasias de la Vejiga Urinaria/etiología , Neoplasias Urológicas/etiología , Anciano , Estudios de Casos y Controles , China , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias Urológicas/diagnósticoRESUMEN
Dicer and Argonaute2 (Ago2) are critical components responsible not only for RNA interference but also for microRNA synthesis. The present study investigated the roles of Dicer and Ago2 in prostate cancer (Pca). First, the expression levels of Dicer and Ago2 in Pca tissues were determined by immunohistochemistry (IHC) and compared with pathological features. Next, RNA interference was used to down-regulate the expression levels of Dicer and Ago2 in the Pca cell lines LNCaP, PC-3, and DU145, and effects on proliferation, apoptosis, and cell cycle were detected using the CCK-8 assay and flow cytometry, respectively. We found that Dicer and Ago2 expression levels in Pca tissues were higher than those in adjacent benign tissues and correlated with lower Gleason patterns, with the exception of Dicer expression in localized Pca. In vitro, silencing Dicer or Ago2 inhibited cell proliferation and induced apoptosis in LNCaP, PC-3, and DU145, as well as arrested the cell cycle at the G2/M phase in androgen-dependent LNCaP, or at S phase in the androgen-independent PC-3 and DU145. Altogether these findings suggest that Dicer and Ago2 play important roles in proliferation, apoptosis, and the cell cycle in Pca and might serve as both promising biomarkers for Pca progression and potential therapeutic targets.
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Apoptosis , Proteínas Argonautas/metabolismo , Biomarcadores de Tumor/metabolismo , Proliferación Celular , ARN Helicasas DEAD-box/metabolismo , Neoplasias Hormono-Dependientes/patología , Neoplasias de la Próstata/patología , Ribonucleasa III/metabolismo , Proteínas Argonautas/antagonistas & inhibidores , Proteínas Argonautas/genética , Western Blotting , Ciclo Celular , ARN Helicasas DEAD-box/antagonistas & inhibidores , ARN Helicasas DEAD-box/genética , Humanos , Técnicas para Inmunoenzimas , Masculino , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/metabolismo , Pronóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , ARN Interferente Pequeño/genética , Ribonucleasa III/antagonistas & inhibidores , Ribonucleasa III/genética , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To examine the prevalence of dyslipidaemia in patients with renal cell carcinoma (RCC) in a Chinese population. PATIENTS AND METHODS: In all, 550 histologically confirmed RCC cases and 570 controls, matched for age and sex were included. Total cholesterol, triglyceride, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were assessed before treatment using standard techniques. The lipid profiles were defined as 'normal', 'borderline high', 'high' and 'low' according to Chinese Guidelines on Adult Dyslipidaemia. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression in both unadjusted and adjusted models. RESULTS: Abnormal LDL elevation was common in RCC cases compared with controls (P < 0.001). Results for total cholesterol, triglyceride and HDL levels between groups were insignificant. The OR for RCC for high levels of LDL (≥160 mg/dL) compared with those with a normal LDL profile was 4.675 (95% CI 1.900-11.500). After adjustment for age, gender, body mass index, smoking status, hypertension, diabetes, total cholesterol and triglyceride, the coexistence of high levels of LDL and RCC was large and statistically significant (OR 8.955, 95% CI 3.371-23.786). There was a significant coexistence of RCC for participants with high LDL levels when subgroups of cases with clear cell subtypes and advanced T stages were compared with controls. CONCLUSION: Abnormal LDL elevation was prevalent in Chinese patients with RCC. The results remain to be evaluated in prospective cohorts.
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Carcinoma de Células Renales/complicaciones , Dislipidemias/epidemiología , Dislipidemias/etiología , Neoplasias Renales/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , China , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios RetrospectivosRESUMEN
BACKGROUND: Metabolic syndrome (MS) is a cluster of metabolic abnormalities, which has been regarded as a pivotal risk factor for cardiovascular diseases. Recent studies focusing on the relationship between MS and cancer have recognized the significant role of MS on carcinogenesis. Likewise, growing evidence suggests that MS has a strong association with increased renal cell carcinoma (RCC) risk. This review outlines the link between MS and RCC, and some underlying mechanisms responsible for MS-associated RCC. MATERIALS AND METHODS: A National Center for Biotechnology Information PubMed search (http://www.pubmed.gov) was conducted using medical subject headings 'metabolic syndrome', 'obesity', 'hypertension', 'diabetes', 'dyslipidemia', and 'renal cell carcinoma'. RESULTS: This revealed that a variety of molecular mechanisms secondary to MS are involved in RCC formation, progression, and metastasis. A deeper understanding of these molecular mechanisms may provide some strategies for the prevention and treatment of RCC. CONCLUSIONS: In summary, there is a large body of evidence regarding the link between MS and RCC, within which each component of MS is considered to have a close causal association with RCC.
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Carcinoma de Células Renales/etiología , Neoplasias Renales/etiología , Síndrome Metabólico/complicaciones , Humanos , Factores de RiesgoRESUMEN
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an uncommon and highly aggressive malignancy with undetermined histogenesis and poor prognosis. To date, no case of testicular DSRCT has been reported in the literature. CASE: A 42-year-old Chinese man presented with painless swelling of his left testis and a painless palpable nodule in his left inguinal region. Computed tomography showed a solid mass in the left testis and multiple metastases in the body. Laboratory tests gave no abnormal results. Left radical orchiectomy was performed, and histopathological and molecular pathological examination showed typical features of DSRCT. Six cycles of chemotherapy were administrated after the operation, leading to partial remission. Postoperative 9-month follow-up indicated no progression.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tumor Desmoplásico de Células Pequeñas Redondas/patología , Orquiectomía , Neoplasias Testiculares/patología , Adulto , Terapia Combinada , Tumor Desmoplásico de Células Pequeñas Redondas/terapia , Humanos , Masculino , Pronóstico , Neoplasias Testiculares/terapia , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: To investigate the influence of anthropometric measures of obesity, including body mass index (BMI), abdominal subcutaneous adipose tissue and visceral adipose tissue, on pathological characteristics in patients with clinically localized prostate cancer. METHODS: From January 2006 to March 2013, the 413 patients of prostate cancer who received radical prostatectomy (RP) and their clinical and pathological data had been collected. The median age for the entire cohort was 68 years, which ranged from 48 to 78 years. All patients were diagnosed with prostate cancer before surgery and the Gleason score ranged from 4 to 10 (median 7). Anthropometric measures of abdominal adiposity including anterior abdominal fat, posterior abdominal fat and anteroposterior diameter were measured from the T2 weighted sagittal localization images of MRI scans and subcutaneous adipose tissue and the percentage of visceral adipose tissue were calculated. The patients' clinical and pathologic characteristics across BMI groups were compared used Student's t test for continuous variables or chi-squared test for categorical variables. Moreover, univariable and multivariable logistic regression models were used to address the influence of anthropometric measures of obesity on pathological outcomes. RESULTS: The BMI ranged from 14.2 to 34.0 kg/m(2) and the median value was 23.8 kg/m(2). The abdominal subcutaneous adipose tissue ranged from 12.6 to 60.3 mm and the median value was 31.4 mm. The percentage of visceral adipose tissue ranged from 71.1% to 92.1% and the median value was 83.8%. In RP specimens, Gleason score ≥ 8 was observed in 141 patients (34.1%), pathological tumor stage was T3a in 69 patients (16.7%) and pathological tumor stage was T3b in 78 patients (18.9%). Positive surgical margin and lymph node involvement were observed in 71(17.2%) and 38(9.2%) patients, respectively. Although univariate analysis showed that BMI ≥ 25 kg/m(2) was associated with pathological Gleason score ≥ 8 (OR = 1.413, P = 0.035), this positive correlation disappeared in multivariate analysis(P = 0.095). In multivariate analysis, the percentage of visceral adipose tissue was significantly associated with pathological Gleason score (OR = 9.618, P = 0.000), extracapsular extension (OR = 6.750, P = 0.002) and seminal vesicle invasion (OR = 4.419, P = 0.007) after adjusting for patient age, PSA level, clinical stage and biopsy Gleason score. CONCLUSIONS: Anthropometric measures of abdominal adiposity was more sophisticated than simple BMI to evaluate the risk of obesity with regard to the aggressiveness of prostate cancer. The percentage of visceral adipose tissue was an independent factor for pathological Gleason score, extracapsular extension and seminal vesicle invasion in RP specimens.
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Obesidad/complicaciones , Próstata/patología , Neoplasias de la Próstata/patología , Adiposidad , Anciano , Antropometría , Índice de Masa Corporal , Humanos , Grasa Intraabdominal , Modelos Logísticos , Masculino , Persona de Mediana Edad , Prostatectomía , Factores de RiesgoRESUMEN
OBJECTIVE: To observe the current changes of voltage-dependent potassium channel (Kv1.3 potassium channel) and calcium-activated potassium channel (IKCa1 potassium channel) in peripheral blood T-lymphocyte derived from hypertensive patients of Xinjiang Kazakh. METHODS: Twenty randomly selected untreated Kazakh hypertensive patients and 20 Kazakh healthy subjects from Xinjiang were included in this study. T-lymphocytes were isolated from peripheral blood with magnetic cell sorting, the whole-cell currents of Kv1.3 and IKCa1 potassium channels were recorded with patch-clamp technique. RESULTS: (1) The current density of Kv1.3 potassium channel was significantly higher in the hypertensive group [(280 ± 74) pA/pF (n = 39)] than that in the control group [(179 ± 51) pA/pF (n = 38), P < 0.01], while the membrane capacitance was similar between the two groups. (2) The current density of IKCa1 potassium channel was also significantly higher in the hypertensive group [(198 ± 44) pA/pF (n = 28)] than that in the control group [(124 ± 43) pA/pF (n = 26), P < 0.01], while the membrane capacitance was also similar between the two groups. CONCLUSIONS: The T-lymphocytes Kv1.3 potassium channel and IKCa1 potassium channel current densities are higher in hypertensive patients in Xinjiang Kazakh suggesting a potential role of Kv1.3 and IKCa1 potassium channels activation in the pathophysiology of hypertension.