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1.
J Transl Med ; 22(1): 538, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844946

RESUMO

Apalutamide, a novel endocrine therapy agent, has been shown to significantly improve the prognosis of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, resistance to apalutamide has also been reported, and the underlying mechanism for this response has yet to be clearly elucidated. First, this study established apalutamide-resistant prostate cancer (PCa) cells, and confirmed that apalutamide activated the release of calcium ions (Ca2+) and endoplasmic reticulum stress (ERS) to enhance autophagy. Second, RNA sequencing, western blotting, and immunohistochemistry revealed significantly decreased Calpain 2 (CAPN2) expression in the apalutamide-resistant PCa cells and tissues. Furthermore, immunofluorescence and transmission electron microscopy (TEM) showed that CAPN2 promoted apalutamide resistance by activating protective autophagy. CAPN2 promoted autophagy by reducing Forkhead Box O1 (FOXO1) degradation while increasing nuclear translocation via nucleoplasmic protein isolation and immunofluorescence. In addition, FOXO1 promoted protective autophagy through the transcriptional regulation of autophagy-related gene 5 (ATG5). Furthermore, a dual-fluorescence assay confirmed that transcription factor 3 (ATF3) stimulation promoted CAPN2-mediated autophagy activation via transcriptional regulation. In summary, CAPN2 activated protective autophagy by inhibiting FOXO1 degradation and promoting its nuclear translocation via transcriptional ATG5 regulation. ATF3 activation and transcriptional CAPN2 regulation jointly promoted this bioeffect. Thus, our findings have not only revealed the mechanism underlying apalutamide resistance, but also provided a promising new target for the treatment of metastatic PCa.


Assuntos
Autofagia , Calpaína , Resistencia a Medicamentos Antineoplásicos , Metástase Neoplásica , Neoplasias da Próstata , Tioidantoínas , Humanos , Masculino , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Calpaína/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Tioidantoínas/farmacologia , Tioidantoínas/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína Forkhead Box O1/metabolismo , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Animais
3.
Int J Med Sci ; 17(10): 1366-1374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32624693

RESUMO

Background: To explore the prediction value of PI-RADS v2 in high-grade prostate cancer and establish a prediction model combined with related variables of prostate cancer. Material and Methods: A total of 316 patients with newly discovered prostate cancer at Zhongnan Hospital of Wuhan University and Renmin Hospital of Wuhan University from December 2017 to August 2019 were enrolled in this study. The clinic information as age, tPSA, fPSA, prostate volume, Gleason score and PI-RADS v2 score have been collected. Univariate analysis was performed based on every variable to investigate the risk factors of high-grade prostate cancer. ROC curves were generated for the risk factors to distinguish the cut-off points. Logistic regression analyses were used to investigate the independent risk factors of high-grade prostate cancer. Nomogram prediction model was generated based on multivariate logistic regression analysis. The calibration curve, ROC curve, leave-one-out cross validation and independent external validation were performed to evaluate the discriminative ability, accuracy and stability of the nomogram prediction model. Results: Of 316 patients, a total of 187 patients were diagnosed as high-grade prostate cancer. Univariate analysis showed tPSA, fPSA, prostate volume, PSAD and PI-RADS v2 score were significantly different between the high- and low-grade prostate cancer patients. Univariate and multivariate logistic regression analyses showed only tPSA, prostate volume and PI-RADS v2 score were the independent risk factors of high-grade prostate cancer. The nomogram could predict the probability of high-grade prostate cancer, with a sensitivity of 79.4% and a specificity of 77.6%. The calibration curve displayed good agreement of the predicted probability with the actual observed probability. AUC of the ROC curve was 0.840 (0.797-0.884). Leave-one-out cross validation indicated the nomogram prediction model could classify 81.4% cases accurately. External data validation was performed with a sensitivity of 80.6% and a specificity of 77.3%, the Kappa value was 0.5755. Conclusions: PI-RADS v2 score had the value in predicting high-grade prostate cancer and the nomogram prediction model may help early diagnose the high risk prostate cancer.


Assuntos
Próstata/patologia , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Humanos , Modelos Logísticos , Imageamento por Ressonância Magnética , Masculino , Estudos Multicêntricos como Assunto , Nomogramas , Próstata/metabolismo , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Estudos Retrospectivos
5.
Molecules ; 21(10)2016 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-27775662

RESUMO

Capsaicin (CAP), a highly selective agonist for transient receptor potential vanilloid type 1 (TRPV1), has been widely reported to exhibit anti-oxidant, anti-inflammation and anticancer activities. Currently, several therapeutic approaches for bladder cancer (BCa) are available, but accompanied by unfavorable outcomes. Previous studies reported a potential clinical effect of CAP to prevent BCa tumorigenesis. However, its underlying molecular mechanism still remains unknown. Our transcriptome analysis suggested a close link among calcium signaling pathway, cell cycle regulation, ROS metabolism and FOXO signaling pathway in BCa. In this study, several experiments were performed to investigate the effects of CAP on BCa cells (5637 and T24) and NOD/SCID mice. Our results showed that CAP could suppress BCa tumorigenesis by inhibiting its proliferation both in vitro and in vivo. Moreover, CAP induced cell cycle arrest at G0/G1 phase and ROS production. Importantly, our studies revealed a strong increase of FOXO3a after treatment with CAP. Furthermore, we observed no significant alteration of apoptosis by CAP, whereas Catalase and SOD2 were considerably upregulated, which could clear ROS and protect against cell death. Thus, our results suggested that CAP could inhibit viability and tumorigenesis of BCa possibly via FOXO3a-mediated pathways.


Assuntos
Capsaicina/administração & dosagem , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Capsaicina/farmacologia , Catalase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Prostate ; 75(1): 33-44, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25307178

RESUMO

BACKGROUND: High Mobility Group N (HMGN) proteins are a family of chromatin structural proteins that specifically bind to nucleosome core particles. HMGN5 is a novel and characteristic member of the HMGN protein family. We have previously found that HMGN5 is upregulated in prostate cancer and its downregulation had been demonstrated to induce apoptosis and G2-M cell cycle arrest. METHODS: The radiosensitization effect of HMGN5 knockdown on PC3 and DU145 cells was assessed using clonogenic assay, flow cytometry, and comet assay. The DNA double-strand break (DSB) repair kinetics of HMGN5 knockdown and control cells after radiation exposure was evaluated using immunocytofluorescence. The mitochondrial reactive oxygen species (ROS) levels were estimated using Dihydrorhodamine 123 (DHR 123) probes. Expression of mitochondrial antioxidant MnSOD was measured by real-time PCR and Western blot. The expression of antiapoptotic proteins Bcl-2 and Bcl-xL as well as cleavage of caspase-3, caspase-9, and PARP were also measured using Western blot. RESULTS: HMGN5 knockdown cells exhibit decreased clonogenic survival and increased apoptosis rate in response to 2-8 Gy ionizing radiation (IR). Loss of HMGN5 does not affect the DSB repair kinetics after radiation exposure. HMGN5 knockdown cells demonstrated increased mitochondrial ROS level and suppressed induction of MnSOD upon radiation compared with control cells upon radiation. Further, MnSOD knockdown resulted in inhibited cell viability as well as increased mitochondrial ROS level and apoptosis upon radiation in PC3 and DU145 cells. Finally, HMGN5 knockdown cells showed significantly decreased levels of antiapoptotic proteins Bcl-2 and Bcl-xL as well as increased cleavage of caspase-3, caspase-9, and PARP compared with control cells after radiation. CONCLUSIONS: HMGN5 knockdown sensitizes prostate cancer cells to ionizing radiation, and the radiosensitization effect may be partially mediated through suppressed induction of MnSOD and enhanced activation of apoptosis pathway in response to IR.


Assuntos
Apoptose/genética , Técnicas de Silenciamento de Genes , Proteínas HMGN/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/radioterapia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Transativadores/genética , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Citometria de Fluxo , Imunofluorescência , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/patologia , Radiação Ionizante , Radiossensibilizantes , Reação em Cadeia da Polimerase em Tempo Real , Ensaio Tumoral de Célula-Tronco
7.
Tumour Biol ; 36(2): 1251-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25344677

RESUMO

Potassium inwardly rectifying channel, subfamily J, member 1 (KCNJ1), as an ATP-dependent potassium channel, plays an essential role in potassium balance. KCNJ1 variation is associated with multiple diseases, such as antenatal Bartter syndrome and diabetes. However, the role of KCNJ1 in clear cell renal cell carcinoma (ccRCC) is still unknown. Here, we studied the expression and function of KCNJ1 in ccRCC. The expression of KCNJ1 was evaluated in ccRCC tissues and cell lines by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry analysis. The relationship between KCNJ1 expression and clinicopathological characteristics was analyzed. p3xFLAG-CMV-14 vector containing KCNJ1 was constructed and used for transfecting ccRCC cell lines 786-O and Caki-2. The effects of KCNJ1 on cell proliferation, invasion, and apoptosis were detected in ccRCC cell lines using cell proliferation assay, transwell assay, and flow cytometry, respectively. We found that KCNJ1 was low-expressed in ccRCC tissues samples and cell lines, and its expression level was significantly associated with tumor pathology grade (P = 0.002) and clinical stage (P = 0.023). Furthermore, the KCNJ1 expression was a prognostic factor of ccRCC patient's survival (P = 0.033). The re-expression of KCNJ1 in 786-O and Caki-2 significantly inhibited cancer cell growth and invasion and promoted cancer cell apoptosis. Moreover, knockdown of KCNJ1 in HK-2 cells promoted cell proliferation. Collectively, these data highlight that KCNJ1, low-expressed in ccRCC and associated with poor prognosis, plays an important role in ccRCC cell growth and metastasis.


Assuntos
Apoptose/genética , Carcinoma de Células Renais/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Prognóstico , Adulto , Idoso , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Canais de Potássio Corretores do Fluxo de Internalização/biossíntese
8.
BMC Cancer ; 15: 380, 2015 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-25956057

RESUMO

BACKGROUND: To analyze the expression of karyopherin alpha 2 (KPNA2) in upper tract urothelial carcinoma (UTUC) and to investigate whether the KPNA2 expression provides additional prognostic information following radical nephroureterectomy (RNU). METHODS: A tissue microarray (TMA) containing samples from 176 patients with UTUC who underwent RNU at our institute was analyzed for KPNA2 expression using immunohistochemistry. KPNA2 expression in normal urothelial cell line and urothelial carcinoma cell lines was evaluated by western blot analysis. Using RNA interference in vitro, the effects of KPNA2 inhibition on cellular viability, migration and apoptosis were determined. RESULTS: KPNA2 expression was significantly upregulated in the UTUC samples compared with the adjacent normal urothelial tissues. High KPNA2 immunoreactivity was identified as a predictor of bladder recurrence (hazard ratio [HR]: 2.017, 95% CI 1.13-3.61, p = 0.018), poor disease-free survival (DFS, HR: 2.754, 95% CI 1.68-4.51, p = 0.001) and poor overall survival (OS, HR: 4.480, 95% CI 1.84-10.89, p = 0.001) for patients with UTUC after RNU. Furthermore, high KPNA2 immunoreactivity was independent of the conventional predictive factors in a multivariate analysis. Additional in vitro experiments revealed that KPNA2 expression was higher in urothelial carcinoma cell lines than in normal urothelial cell line. KPNA2 inhibition with a specific siRNA decreased cell viability and migration and increased apoptosis in urothelial carcinoma cell lines. CONCLUSIONS: KPNA2 is a novel independent prognostic marker for bladder recurrence, DFS and OS of UTUC patients who have undergone RNU. Moreover, these data suggest that KPNA2 may be a promising therapeutic target for UTUC.


Assuntos
Carcinoma de Células de Transição/metabolismo , Recidiva Local de Neoplasia/metabolismo , Neoplasias Ureterais/metabolismo , alfa Carioferinas/metabolismo , Idoso , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Intervalo Livre de Doença , Feminino , Expressão Gênica , Humanos , Masculino , Recidiva Local de Neoplasia/mortalidade , Nefrectomia , Prognóstico , Modelos de Riscos Proporcionais , Ureter/patologia , Ureter/cirurgia , Neoplasias Ureterais/mortalidade , Neoplasias Ureterais/patologia , Neoplasias Ureterais/cirurgia , alfa Carioferinas/genética
9.
Mol Cancer ; 13: 206, 2014 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-25193015

RESUMO

BACKGROUND: MicroRNAs are endogenous small noncoding RNAs that are functionally involved in numerous critical cellular processes including tumorigenesis. Data mining using a microRNA array database suggested that let-7d microRNA may be associated with renal cell carcinoma (RCC) malignant progression. Here, we performed further analyses to determine whether let-7d is functionally linked to RCC malignancy. METHODS: Quantitative real-time PCR was used to determine the level of mature let-7d in RCC clinical specimens and its correlation with clinicopathological data. Immunohistochemical staining was conducted to characterize the stroma of RCC. Let-7d overexpressing RCC cell lines combined with mouse models bearing cell-derived xenografts and patient-derived xenografts were used to assess the functional role of let-7d in vitro and in vivo. RESULTS: Downregulation of let-7d in clinical RCC samples was associated with advanced tumor grade and T stage and increased vascular invasion. An inverse relationship between let-7d expression and macrophage infiltration was found in clinical RCC samples. Functional studies indicated that ectopic expression of let-7d significantly inhibited RCC cell proliferation, migration, and peripheral blood monocyte (PBMC) recruitment in vitro, as well as tumor growth, metastasis, and tumor macrophage infiltration in vivo. In silico analysis and subsequent experimental validation confirmed collagen, type III, alpha 1 (COL3A1) and C-C subfamily chemokine member CCL7 as direct let-7d target genes. The addition of COL3A1 and CCL7 counteracted the inhibitory effects of let-7d on RCC cell proliferation, migration, and PBMC recruitment. The inhibition of let-7d increased cell proliferation, migration, and PBMC recruitment by the enhanced expression of COL3A1 and CCL7 genes in vitro. The mRNA levels of COL3A1 and CCL7 were inversely correlated with let-7d level in RCC clinical specimens. CONCLUSIONS: These results suggest that let-7d may suppress RCC growth, metastasis, and tumor macrophage infiltration at least partially through targeting COL3A1 and CCL7.


Assuntos
Carcinoma de Células Renais/patologia , Quimiocina CCL7/genética , Colágeno Tipo III/genética , Neoplasias Renais/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Idoso , Animais , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Experimentais
10.
Int J Mol Sci ; 14(11): 21215-26, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-24284390

RESUMO

Kaempferol (Kae), a natural flavonoid, is widely distributed in fruits and vegetables. Previous studies have identified Kae as a possible cancer preventive and therapeutic agent. We found Kae to exhibit potent antiproliferation and anti-migration effects in human bladder cancer EJ cells. Kaempferol robustly induced apoptosis in EJ cells in a dose-dependent manner, as evidenced by increased cleavage of caspase-3. Furthermore, we found Kae-induced apoptosis in EJ cells to be associated with phosphatase and the tensin homolog deleted on the chromosome 10 (PTEN)/PI3K/Akt pathway. Kae significantly increased PTEN and decreased Akt phosphorylation. Kae-induced apoptosis was partially attenuated in PTEN-knockdown cells. Our findings indicate that Kae could be an alternative medicine for bladder cancer, based on a PTEN activation mechanism.


Assuntos
Apoptose/efeitos dos fármacos , Quempferóis/administração & dosagem , PTEN Fosfo-Hidrolase/biossíntese , Neoplasias da Bexiga Urinária/tratamento farmacológico , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias da Bexiga Urinária/patologia
11.
Front Cardiovasc Med ; 9: 1092260, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36601067

RESUMO

Pheochromocytomas are neuroendocrine tumors that produce catecholamines and can be difficult to diagnose. Bladder involvement is uncommon with pheochromocytoma. Hypertension (sometimes with hypertensive crisis coinciding with micturition), headache, hematuria and syncope, which are commonly associated with voiding, are the most prevalent symptoms. While transurethral resection may be performed in roughly 20% of patients, 70% require partial cystectomy and 10% require radical cystectomy. We present a case of pheochromocytoma with hypertension and syncope that was often associated with voiding, satisfactorily treated by partial cystectomy.

12.
Clin Transl Med ; 12(8): e1008, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35968916

RESUMO

BACKGROUND: State-of-art non-invasive diagnosis processes for bladder cancer (BLCA) harbour shortcomings such as low sensitivity and specificity, unable to distinguish between high- (HG) and low-grade (LG) tumours, as well as inability to differentiate muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). This study investigates a comprehensive characterization of the entire DNA methylation (DNAm) landscape of BLCA to determine the relevant biomarkers for the non-invasive diagnosis of BLCA. METHODS: A total of 304 samples from 224 donors were enrolled in this multi-centre, prospective cohort study. BLCA-specific DNAm signature discovery was carried out with genome-wide bisulfite sequencing in 32 tumour tissues and 12 normal urine samples. A targeted sequencing assay for BLCA-specific DNAm signatures was developed to categorize tumour tissue against normal urine, or MIBC against NMIBC. Independent validation was performed with targeted sequencing of 259 urine samples in a double-blinded manner to determine the clinical diagnosis and prognosis value of DNAm-based classification models. Functions of genomic region harbouring BLCA-specific DNAm signature were validated with biological assays. Concordances of pathology to urine tumour DNA (circulating tumour DNA [ctDNA]) methylation, genomic mutations or other state-of-the-art diagnosis methods were measured. RESULTS: Genome-wide DNAm profile could accurately classify LG tumour from HG tumour (LG NMIBC vs. HG NMIBC: p = .038; LG NMIBC vs. HG MIBC, p = .00032; HG NMIBC vs. HG MIBC: p = .82; Student's t-test). Overall, the DNAm profile distinguishes MIBC from NMIBC and normal urine. Targeted-sequencing-based DNAm signature classifiers accurately classify LG NMIBC tissues from HG MIBC and could detect tumours in urine at a limit of detection of less than .5%. In tumour tissues, DNAm accurately classifies pathology, thus outperforming genomic mutation or RNA expression profiles. In the independent validation cohort, pre-surgery urine ctDNA methylation outperforms fluorescence in situ hybridization (FISH) assay to detect HG BLCA (n = 54) with 100% sensitivity (95% CI: 82.5%-100%) and LG BLCA (n = 26) with 62% sensitivity (95% CI: 51.3%-72.7%), both at 100% specificity (non-BLCA: n = 72; 95% CI: 84.1%-100%). Pre-surgery urine ctDNA methylation signature correlates with pathology and predicts recurrence and metastasis. Post-surgery urine ctDNA methylation (n = 61) accurately predicts recurrence-free survival within 180 days, with 100% accuracy. CONCLUSION: With the discovery of BLCA-specific DNAm signatures, targeted sequencing of ctDNA methylation outperforms FISH and DNA mutation to detect tumours, predict recurrence and make prognoses.


Assuntos
DNA Tumoral Circulante , Neoplasias da Bexiga Urinária , Biomarcadores Tumorais/genética , Metilação de DNA/genética , Humanos , Hibridização in Situ Fluorescente , Estudos Prospectivos , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
13.
Int J Biol Sci ; 17(5): 1250-1262, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33867843

RESUMO

The purpose of our study was to explore the effect and intrinsic mechanism of wild-type IDH1 and its substrate α-KG on renal cell carcinoma (RCC). IDH1 was observed lower expression in RCC cell lines. Phenotype experiment was carried out in the wild-type IDH1 and mutant IDH1R132H plasmid treated cell line. The results showed that the wild-type IDH1 could significantly inhibit the proliferation, migration and promote the apoptosis of RCC cell lines, which were consistent with the IDH1's substrate α-KG. The mutant IDH1R132H was found to lose this biological function of IDH1. Moreover, we verified the proliferation inhibition of IDH1 in vivo. In addition, we verified the correlation between IDH1 and hypoxia signal-related proteins in vitro and in vivo, specifically, IDH1 overexpression could significantly reduce the expression of HIF-1α and HIF-2α proteins and its downstream proteins (VEGF, TGF-α). Furthermore, we preliminarily verified the possibility of α-KG in the RCC's treatment by injecting α-KG into the xenograft model. α-KG significantly reduced tumor size and weight in tumor-bearing mice. This study provided a new therapeutic target and small molecule for the study of the treatment and mechanism of RCC.


Assuntos
Carcinoma de Células Renais , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isocitrato Desidrogenase/metabolismo , Neoplasias Renais , Animais , Apoptose , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular , Descoberta de Drogas , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Camundongos , Fator de Crescimento Transformador alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Front Oncol ; 11: 796975, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35127507

RESUMO

OBJECTIVE: Limited attention has been paid to abnormal blood and urine test results for patients with bladder cancer. The present study aimed to identify whether blood and urine parameters are associated with bladder cancer. METHODS: We used a case-control design and matched each patient with bladder cancer with three healthy controls of the same age and sex. Univariate conditional logistic regression was used to calculate the crude and adjusted odds ratio (OR) and its 95% CI. Multivariate conditional logistic regression was performed for confounders adjustment, and Spearman's correlation coefficient was used to assess the correlation between tumor T stages and urine parameters. RESULTS: Patients with bladder cancer (n = 360) and controls (n = 1050) were recruited. In the univariate conditional logistic analysis, higher urine pH was associated with a decreased risk of bladder cancer (OR = 0.67, 95% CI = 0.57-0.78), while higher values of urine protein (OR = 4.55, 95% CI = 3.36-6.15), urine glucose (OR = 1.56, 95% CI = 1.18-2.05), and urine occult blood (OR = 4.27, 95% CI = 3.44-5.29) were associated with an increased risk of bladder cancer. After adjustment for body mass index, fasting blood glucose, hypertension, red blood cells, white blood cells, lymphocytes, neutrophils, and platelets, significance still remained for urine pH (OR = 0.68, 95% CI = 0.53-0.88), urine protein (OR = 1.97, 95% CI = 1.21-3.19), urine glucose (OR = 2.61, 95% CI = 1.39-4.89), and urine occult blood (OR = 3.54, 95% CI = 2.73-4.58). CONCLUSION: This study indicated that lower urine pH and higher values of urine protein, urine glucose, and urine occult blood might be risk factors for bladder cancer.

15.
Biotechnol Appl Biochem ; 57(1): 17-24, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20718711

RESUMO

Plasminogen K5 (kringle 5) has strong inhibitory effects on endothelial-cell proliferation and migration. It was reported that K5 can reduce tumour neovascularization, resulting in clinically relevant antitumour effects. To determine whether addition of a tumour-targeting peptide could improve the tumour homing and antitumour activities of K5, we genetically modified K5 with an RGD (Arg-Gly-Asp) motif, which is a ligand with high affinity for αvß3 and αvß5 integrins. The fusion protein RGD-K5 was expressed in the Pichia pastoris system and the biological activity of RGD-K5 was assessed in vitro and in vivo. The results showed that the RGD-K5 exhibited a more potent effect of inhibiting endothelial cell proliferation and migration compared with that of traditional K5. RGD-K5 also displayed stronger anti-angiogenic activity in a CAM (chick chorioallantoic membrane) assay. Furthermore, RGD-K5 also showed stronger anti-angiogenic and antitumour effects in B16F10 melanoma-bearing mice compared with traditional K5. In conclusion, the biological activity of K5 can be further improved by the addition of a tumour-homing peptide, and the RGD-K5 may prove to be a promising novel candidate for cancer therapy.


Assuntos
Oligopeptídeos/química , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Plasminogênio/química , Plasminogênio/farmacologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia , Animais , Anticorpos/isolamento & purificação , Vacinas Anticâncer/biossíntese , Vacinas Anticâncer/química , Vacinas Anticâncer/genética , Linhagem Celular Tumoral , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Clonagem Molecular , Feminino , Histocitoquímica , Humanos , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/efeitos dos fármacos , Oligopeptídeos/biossíntese , Oligopeptídeos/genética , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/genética , Pichia/genética , Plasminogênio/biossíntese , Plasminogênio/genética , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Cancer ; 11(15): 4324-4331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32489451

RESUMO

Objective: To explore the independent risk factors of infection during the intravesical instillation of bladder cancer and establish a prediction model, which may reduce probability of infection for bladder cancer patients. Material and Methods: 533 patients with newly discovered NMIBC at two hospitals from January 2017 to December 2019 were enrolled in this study. The patients were divided into "infection positive group" and "infection negative group". The clinical data of the two groups were analyzed by logistic regression analyses. Nomogram was generated and ROC curve, calibration curve were structured to assess the accuracy of nomogram. An independent cohort included 174 patients from another hospital validated the nomogram prediction model. Results: Of 533 patients, 185 patients had an infection. Univariate and multivariate logistic regression analyses showed diabetes mellitus, hemiplegia, patients without antibiotics and perfusion frequency (≥2 times/month) were the independent risk factors. AUC of the ROC was 0.858 (0.762-0.904). The nomogram could predict the probability of infection during the intravesical instillation of bladder tumor calibration curve showed good agreement. The external data validation gained good sensitivity and specificity, which indicated that the nomogram had great value of prediction. Conclusions: Individualized prediction of the probability of infection may reduce the incidence of infection by argeted preventive measures.

17.
J Cancer ; 11(5): 1212-1222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31956367

RESUMO

5-hydroxymethylcytosine (5hmC) is converted from DNA methylation of cytosine (5mC) by the catalysis of TET proteins, and proposed to be involved in tumorigenesis. However, the prognostic value of 5hmC in renal cell carcinoma (RCC) is still unclear. This study aimed to define the clinical significance of 5hmC in RCC. We performed dot blot assays to measure the relative expression of 5hmC in RCC. We reviewed the clinical records of 310 RCC patients and performed immunohistochemical (IHC) staining of 5hmC. The overall survival (OS) and cancer specific survival (CSS) of all patients were recorded over a 10-year follow-up period. Effective prognostic nomograms which contained 5hmC were established to provide individualized OS and CSS in RCC. 5hmC expression level was significantly decreased in RCC tissues compared with those in the normal counterparts. Kaplan-Meier curves revealed that high 5hmC expression had a good prognostic impact on RCC patients. Cox multivariate survival analyses further indicated 5hmC was an independent prognostic factor for RCC survival. Nomograms constructed based on cox regression analysis were available to calculate the survival probability directly. Calibration curves displayed good agreements. The findings were validated with an independent external cohort included 77 RCC cases. Thus, we believe we have found a significative prognostic factor for RCC.

18.
J Med Chem ; 63(9): 4849-4866, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32297747

RESUMO

Speckle-type POZ protein (SPOP) is overexpressed in the nucleus and misallocated in the cytoplasm in almost all the clear-cell renal cell carcinomas (ccRCCs), which leads to kidney tumorigenesis. Previously, we elucidated that the oncogenic SPOP-signaling pathway in ccRCC could be suppressed by 6b that inhibits SPOP-mediated protein interactions. Herein, we have established a structure-activity relationship for 6b analogues as SPOP inhibitors. Compound 6lc suppresses the viability and inhibits the colony formation of ccRCC cell lines driven by cytoplasmic SPOP, superior to 6b. Compound 6lc binds to the SPOP protein in vitro and disrupts SPOP binding to phosphatase-and-tensin homologue (PTEN) in HEK293T cells, which causes the observable phenomena: a decline in the ubiquitination of PTEN, elevated levels of both PTEN and dual-specificity phosphatase 7, and decreased levels of phosphorylated AKT and ERK when ccRCC cell lines are exposed to 6lc in a dose-response manner. Taken together, compound 6lc is a potent candidate against kidney tumorigenesis.


Assuntos
Antineoplásicos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Piridinas/farmacologia , Pirimidinonas/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Neoplasias Renais/tratamento farmacológico , Estrutura Molecular , Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Ligação Proteica/efeitos dos fármacos , Piridinas/síntese química , Pirimidinonas/síntese química , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade
19.
Oncol Rep ; 40(2): 726-736, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29917166

RESUMO

The mechanisms of malignant cell metastasis to secondary sites are complex and multifactorial. Studies have demonstrated that small integrin­binding ligand N­linked glycoproteins (SIBLINGs), particularly bone sialoprotein (BSP) and osteopontin (OPN), are involved in neoplastic growth and metastasis. SIBLINGs promote malignant cell invasion and metastasis by enhancing matrix metalloproteinase 2 (MMP­2) and MMP­9 expression. Moreover, BSP and OPN can combine with integrin, which is located on the tumor cell surface, to further promote the malignant behavior of tumor cells. In the present study, we investigated whether SB225002, a specific CXCR2 receptor antagonist, can inhibit prostate cancer cell expression of BSP and OPN and reduce cancer cell invasion ability. A series of experiments showed that after SB225002 treatment, the proliferation, invasion and migration of two androgen­independent prostate cancer cell lines were inhibited, but this inhibitory effect was not observed on androgen­dependent prostate cancer cells. Western blotting showed that the PI3K signaling pathway could regulate the expression of SIBLING and MMP family proteins, and SB22055 could reduce the expression of BSP, OPN and MMP­2 in prostate cancer cells by inhibiting AKT/mTOR phosphorylation. Finally, in vivo experiments confirmed that SB225002 inhibited the proliferation of prostate cancer cells in vivo, and the expression levels of BSP, OPN and MMP­2 were also inhibited.


Assuntos
Sialoproteína de Ligação à Integrina/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Invasividade Neoplásica/patologia , Osteopontina/metabolismo , Compostos de Fenilureia/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
20.
Medicine (Baltimore) ; 96(11): e6126, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28296724

RESUMO

Playing critical roles in immune responses, interleukin-6 (IL-6) has been proposed to be involved in the development of multiple cancers, including prostate cancer. The rs1800795 polymorphism in the promoter of the gene IL-6 can affect the transcription and expression of the gene, becoming a common target in association studies on tumors. We therefore carried out this meta-analysis to further discuss the relationship of this polymorphism with the risk of prostate cancer.Relevant publications were retrieved from the electronic databases. The strength of the correlation between IL-6 rs1800795 polymorphism and prostate cancer risk was evaluated using pooled odds ratios (ORs) with their 95% confidence intervals (95% CIs). Q test was adopted to examine between-study heterogeneity, with P < 0.05 as significant level. Subgroup and meta-regression analyses were conducted to explore potential source of heterogeneity. Sensitivity analysis was implemented to test the statistical stability of the final results. In addition, funnel plot and Egger test were employed to inspect publication bias among included studies.A total of 13 132 cases and 15 282 controls were ultimately incorporated into the present study. Overall estimates revealed no significant relationship between IL-6 rs1800795 polymorphism and prostate cancer risk in total analysis, but a risk-increasing effect of the polymorphism was detected in African-American subgroup under CC versus GG and CC versus GG + GC contrasts (OR 3.43, 95% CI 1.01-11.71; OR 3.51, 95% CI 1.04-11.82) after subgroup analysis by ethnicity.IL-6 rs1800795 polymorphism may enhance the susceptibility to prostate cancer in African-American men.


Assuntos
Carcinoma/genética , Interleucina-6/genética , Neoplasias da Próstata/genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo Genético
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