RESUMO
OBJECTIVE: To determine the expression of Skp2 in different prostate cancer (PCa) cell lines and tissues, and explore its influence on the androgen receptor (AR) signaling pathway and development of castration-resistant prostate cancer (CRPC). METHODS: The expression levels of Skp2 and AR in different PCa cell lines were detected by Western blot. After knockdown of Skp2 in the C4-2 and 22RV1 cells transfected with shRNA, the expressions of AR and P27 were determined and the activity of ARR3-Luc measured by dual-luciferase reporter gene assay following treatment with dihydrotestosterone (DHT). The expressions of AR and Skp2 in human naïve PCa or CRPC specimens were detected by immunohistochemical staining followed by analysis of their differences and correlation. RESULTS: The Skp2 protein expression level was significantly higher in the C4-2 or 22RV1 cells than in the LNCaP cells. DHT treatment increased the expression of Skp2 in the C4-2 cells, but knock-down of Skp2 significantly up-regulated the expression of the well-known downstream protein P27 and down-regulated that of AR. Consistently, DHT treatment increased the activity of ARR3-Luc, while knockdown of Skp2 remarkably decreased it in the C4-2 and 22RV1 cells (P < 0.05). In addition, significantly higher expressions of Skp2 and AR were observed in the CRPC than in the naïve specimens (P < 0.05), with a positive correlation between the two proteins (r = 0.658 1, P < 0.05). CONCLUSION: Skp2 can enhance the expression and transcription activity of the AR protein in CRPC cells or tissues and is promising to be a critical molecular therapeutic target.
Assuntos
Proteínas de Neoplasias/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Proteínas Quinases Associadas a Fase S/fisiologia , Androgênios/farmacologia , Linhagem Celular Tumoral , Di-Hidrotestosterona/farmacologia , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Masculino , Proteínas de Neoplasias/genética , Receptores Androgênicos/genética , Ativação Transcricional , Regulação para CimaRESUMO
OBJECTIVE: To investigate the expression of DAB2IP in bladder transitional cell carcinoma (BTCC) and its correlation with clinical characteristics and prognosis of BTCC patients. METHODS: Immunohistochemical staining was applied to detect DAB2IP protein level in 79 cases of TCCB tissues and 11 cases of normal bladder tissues, and the relationships of the staining results with pathological grade, stage, lymph node metastasis, gender, age and the 3-year survival rate of the patients were analyzed. RESULTS: The expression of DAB2IP in BTCC tissues was significantly lower than that in normal bladder epithelium, and the expression score and rate of DAB2IP in the high-grade, invasive and metastatic BTCC were significantly lower than those in low-grade, superficial and non-metastatic BTCC (P < 0.05). The 3-year survival rate of the patients with high DAB2IP expression was significantly higher than that of the patients with low DAB2IP expression. CONCLUSION: DAB2IP may be one of the important inhibitory factors during the occurrence and progression of BTCC.
Assuntos
Carcinoma de Células de Transição/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Carcinoma de Células de Transição/patologia , Progressão da Doença , Humanos , Metástase Linfática , Prognóstico , Neoplasias da Bexiga Urinária/patologia , Urotélio/metabolismoRESUMO
Prostate cancer generally relapses into castration resistant prostate cancer (CRPC) after androgen deprivation therapy, which may be associated with androgen metabolism, particularly de novo androgen synthesis apart from the amplification and mutation of androgen receptor and the activation of its signaling pathways. This article focuses on the advances in the studies of the changes in androgen metabolism and de novo androgen synthesis in CRPC as well as their possible mechanisms and clinical significance.
Assuntos
Androgênios/biossíntese , Androgênios/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Antagonistas de Androgênios/farmacologia , Humanos , Masculino , Orquiectomia , Próstata/metabolismoRESUMO
OBJECTIVE: To explore the roles of intracellular cholesterol metabolism in neuroendocrine (NE) differentiation of prostate cancer based on an androgen-independent prostate cancer NE cell model induced by androgen deprivation. METHODS: LNCaP cells were cultured in androgen-depleted medium, and NE phenotypes were identified by observing the changes in cell morphology, molecular markers (SgIII, NSE and CgA) and cell proliferation. The expression and distribution of cholesterol and Sg III were determined by immunofluorescence staining. The expressions of the key genes LDL-R, SREBP-1 and SREBP-2 involved in cholesterol synthesis and uptake were detected by semi-quantitative RT-PCR. RESULTS: The LNCaP cells showed shrinking bodies and extending axons after androgen deprivation, and all the molecular markers, such as Sg III, NSE and CgA, significantly increased in a time-dependent manner, while the cell proliferation was obviously inhibited (P < 0.05). The cholesterol distribution in the LNCaP cells after NE differentiation presented remarkable aggregation at the axon terminals. However, there were no significant differences in the expression of cholesterol between the two types of cells, nor in the changes of the expressions of key genes LDL-R, SREBP-1 and SREBP-2 involved in cholesterol synthesis and uptake (P > 0.05). CONCLUSION: Transient androgen depletion could successfully induce NE differentiation of LNCaP cells, and the intracellular cholesterol could re-distribute into axon terminals to enhance the formation of neurosecretory granules.
Assuntos
Diferenciação Celular , Colesterol/metabolismo , Sistemas Neurossecretores/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Androgênios/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
AIM: Survivin molecular beacons can be used to detect bladder cancer cells in urine samples non-invasively. The aim of this study is to improve the specificity of detection of bladder cancer cells using survivin dual fluorescence resonance energy transfer molecular beacons (FRET MBs) that have fluorophores forming one donor-acceptor pair. METHODS: Survivin-targeting dual fluorescence resonance energy transfer molecular beacons with unique target sequences were designed, which had no overlap with the other genes in the apoptosis inhibitor protein family. Human bladder cancer cell lines 5637, 253J and T24, as well as the exfoliated cells in the urine of healthy adults and patients with bladder cancer were examined. Images of cells were taken using a laser scanning confocal fluorescence microscope. For assays using dual FRET MBs, the excitation wavelength was 488 nm, and the emission detection wavelengths were 520±20 nm and 560±20 nm, respectively. RESULTS: The human bladder cancer cell lines and exfoliated cells in the urine of patients with bladder cancer incubated with the survivin dual FRET MBs exhibited strong fluorescence signals. In contrast, no fluorescence was detected in the survivin-negative human dermal fibroblasts-adult (HDF-a) cells or exfoliated cells in the urine of healthy adults incubated with the survivin dual FRET MBs. CONCLUSION: The results suggest that the survivin dual FRET MBs may be used as a specific and non-invasive method for early detection and follow-up of patients with bladder cancer.
Assuntos
Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , Transferência Ressonante de Energia de Fluorescência , Humanos , Microscopia Confocal , Microscopia de Fluorescência , Survivina , Neoplasias da Bexiga Urinária/metabolismoRESUMO
OBJECTIVE: To investigate the role and significance of epithelial-mesenchymal transition (EMT) and its transcriptional regulator Twist1 in the development of the human fetal prostate. METHODS: Twenty-five human fetal prostate specimens at various developmental stages (16-39 weeks) were included in this study. EMT markers, such as E-Cadherin, N-Cadherin and Vimentin, and EMT transcriptional regulator Twist1 were determined by immunohistochemistry, and their relationship with the development of the human fetal prostate was analyzed. RESULTS: E-Cadherin was expressed in the fetal prostate epithelium only, while Vimentin, N-Cadherin and Twist1 in both the epithelium and the stroma. The expression of E-Cadherin gradually increased, but those of Vimentin, N-Cadherin and Twist1 gradually decreased with the gestation stages. No significant changes were observed in the staining patterns of Vimentin, N-Cadherin and Twist1 in the stroma during the whole developmental process. CONCLUSION: EMT is involved in the development of the human fetal prostate, which may promote epithelial cell motility to form prostatic bud tubules in early gestation stages and boost the differentiation of prostate epithelia in later stages.
Assuntos
Transição Epitelial-Mesenquimal , Desenvolvimento Fetal , Próstata/crescimento & desenvolvimento , Próstata/metabolismo , Caderinas/metabolismo , Desdiferenciação Celular , Células Epiteliais/metabolismo , Humanos , Masculino , Mesoderma/metabolismo , Proteínas Nucleares/metabolismo , Próstata/embriologia , Proteína 1 Relacionada a Twist/metabolismo , Vimentina/metabolismoRESUMO
OBJECTIVE: To screen and compare the specific transcription factors that repress the epithelial phenotype in epithelial-mesenchymal transition (EMT) in two different human prostate cancer models LNCaP/HIF1alpha and ARCaP. METHODS: We established two different prostate cancer EMT models, LNCaP/HIF1alpha and ARCaP, cultured LNCaP, LNCaP/HIF1alpha, IF11 and IA8 cells in vitro, and detected the five transcription factors Snail, Slug, ZEB1, SIP1 and Twist1 in these cells by RT-PCR. RESULTS: Different levels of Snail, Slug, ZEB1, SIP1 and Twist1 were detected in both LNCaP and LNCaP/HIF1alpha cells, with significant differences only in the expressions of Slug and Twist1 between the two cells. The expression of Slug was increased, but that of Twist1 decreased in the LNCaP/HIF1alpha cells. All the five transcription factors but Twist1 were expressed in both the IF11 and IA8 cells, but only the express- sions of ZEB1 and Slug were increased significantly in the IA8 cells. CONCLUSION: There are different mechanisms underlying transcriptional regulation in different prostate cancer EMT models. Slug may be one of the key transcription factors involved in the HIF1alpha-induced EMT of LNCaP cells, while ZEB1 and Slug may play an important role in repressing the epithelial phenotype of the ARCaP model.
Assuntos
Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Células Estromais/metabolismo , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Masculino , Fenótipo , Neoplasias da Próstata/genética , Células Estromais/citologia , Fatores de Transcrição/classificação , Fatores de Transcrição/genéticaRESUMO
AIM: Silibinin is known to exert growth inhibition and cell death together with cell cycle arrest and apoptosis in human prostate cancer cells. Whether silibinin could inhibit the invasion, motility and migration of prostate cancer cells remains largely unknown. This study was designed to evaluate this efficacy and possible mechanisms using a novel highly bone metastatic ARCaP(M) cell model. METHODS: Four prostate cancer cell lines, LNCaP, PC-3, DU145, and ARCaP(M), were used in this study. These cells were treated with increasing concentrations of silibinin (50, 100, and 200 micromol/L) for different periods of time. After treatment, cell viabilities of four prostate cancer cells were compared by MTT assay. Alterations of ARCaP(M) cell invasion, motility and migration were assessed by cell invasion, motility and wound healing assays. The changes of vimentin expression were observed by Western blotting and immunofluorescence staining, and the expression of MMP-2, MMP-9, and uPA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: ARCaP(M) cells showed less sensitivity to the growth inhibition of pharmacological doses of silibinin than LNCaP, PC-3, and DU145 cells. However, silibinin exerted significant dose- and time-dependent inhibitory effects on the invasion, motility and migration of ARCaP(M) cells. Furthermore, the expression of vimentin and MMP-2, but not MMP-9 or uPA, was down-regulated in a dose- and time-dependent manner after treatment of silibinin. CONCLUSION: This study shows that silibinin could inhibit the invasion, motility and migration of ARCaP(M) cells via down-regulation of vimentin and MMP-2 and therefore may be a promising agent against prostate cancer bone metastasis.
Assuntos
Antioxidantes/uso terapêutico , Movimento Celular/efeitos dos fármacos , Metaloproteinase 2 da Matriz/genética , Invasividade Neoplásica/prevenção & controle , Neoplasias da Próstata/patologia , Vimentina/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Silibina , Silimarina/uso terapêutico , Vimentina/metabolismoRESUMO
AIM: To determine the effect of human DNA binding protein (dbpA) on the biology of gastric cancer cells. METHODS: DbpA expression was analyzed by Western blot analysis and immunofluorescence staining in gastric cancer tissues and cell lines. A dbpA-specific small interference (si) RNA was designed and synthesized. Suppressive effect of siRNA on dbpA expression was assessed by real-time RT-PCR. Transwell migration and colony formation assays were used to assess the inhibitory effects of dbpA siRNA on cell invasion and tumorigenesis in vitro. Drug-sensitivity was evaluated using a conventional 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. RESULTS: The expression of dbpA was upregulated in gastric cancer tissues and cell lines as compared to adjacent normal tissues or gastric epithelial cells. siRNA treatment successfully silenced dbpA expression. Silencing of dbpA increased expression of E-cadherin, decreased expression of adenomatous polyposis coli (APC), beta-catenin and cyclin D1, but had no effect on expression of NF-kappaB. Silencing of dbpA also suppressed cell invasion and colony formation of SGC7901 cells, and enhanced their chemosensitivity to 5-fluorouracil. CONCLUSION: DbpA plays an important role in the pathogenesis and development of gastric cancer, and the process involves E-cadherin, APC, beta-catenin and cyclin D1. Silencing of dbpA might be a novel therapeutic strategy for increasing chemosensitivity to 5-fluorouracil in gastric cancer.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , RNA Interferente Pequeno/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Antineoplásicos/farmacologia , Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Transformada , Linhagem Celular Tumoral , Corantes/metabolismo , Meios de Cultura Livres de Soro , Ciclina D1/genética , Ciclina D1/metabolismo , Técnica Direta de Fluorescência para Anticorpo , Fluoruracila/farmacologia , Proteínas de Choque Térmico/fisiologia , Humanos , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Sais de Tetrazólio/metabolismo , Tiazóis/metabolismo , Transfecção , Regulação para Cima/efeitos dos fármacos , beta Catenina/genética , beta Catenina/metabolismoRESUMO
OBJECTIVE: To observe the expression of Smad4, the core of TGF-beta/Smads signal transduction pathway in different prostate cancer cell lines, and explore their molecular mechanism of bone metastatic potential. METHODS: The Millicell polycarbonate filter coated with matrigel was used to confirm the invasive potency of LNCaP and ARCaP cell lines (IF11 and IA8). The expressions of the Smad4 protein and mRNA in these prostate cancer cells with different metastatic potentials were detected by Western blotting and RT-PCR, respectively. RESULTS: ARCaP cell lines (IF11 and IA8) exhibited a stronger potency of invasion than LNCaP (P < 0.01). The Smad4 protein and mRNA highly expressed in the LNCaP cell line that was well-known with a low metastatic potential, but not in the ARCaP (IF11 or IA8) cells with high metastatic potentials (P < 0.01). CONCLUSION: Smad4 expresses differently in LNCaP and ARCaP cell lines with different metastatic potentials and, as a tumor suppressive gene, its deficient expression may play an important role in the invasion and metastasis of advanced prostate cancer.
Assuntos
Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteína Smad4/biossíntese , Linhagem Celular Tumoral , Humanos , Masculino , Metástase Neoplásica , RNA Mensageiro/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
OBJECTIVE: To determine the TGF-beta/Smads signal pathway in different human prostate cancer cell lines, and to explore the role of the TGF-beta/Smads pathway in the progression and metastasis of prostate cancer and its possible mechanisms. METHODS: We detected the expressions of the key proteins involved in the TGF-beta/Smads pathway, TbetaR II, Smad2/3, p-Smad2 and Smad4, in prostate cancer cell lines LNCaP, PC-3, DU145, IF11 and IA8 with different metastatic potentials by Western blotting. RESULTS: TbetaR II was expressed highly in PC-3, DU145, IF11 and IA8, but extremely lowly in LNCaP. Smad2/3 was highly expressed in all the cell lines with different intensity, while p-Smad2 only in PC-3 and DU145. The expression of Smad4 was detected in LNCaP, PC-3 and DU145, but not in IF11 and IA8. CONCLUSION: The status of the TGF-beta/Smads pathway differs in the cell lines with different metastatic potentials, only active in PC-3 and DU145. The TGF-beta/Smads pathway may be involved in the invasion and metastasis of prostate cancer through altering the expressions of the key proteins in it.
Assuntos
Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Humanos , MasculinoRESUMO
AIM: The aim of the present study was to investigate whether low dose genistein affects the invasion and epithelial mesenchymal transition (EMT) of prostate cancer (PCa) cells. METHODS: Human PCa cell lines, IA8-ARCaP and LNCaP/ HIF-1a, were used in this study. The cell lines were found to process EMT in our previous study. The PCa cells were treated with increasing concentrations, from 0.1 to 75 micromol/L. Proliferation was assessed with 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide assay. EMT was proven by cell morphological transition and the expression changes of EMT-related markers, which were confirmed by RT-PCR, Western blotting, and indirect immunofluorescence labeling. Transwell invasion assay was used to analyze the invasive potency. RESULTS: The addition of genistein to the medium reduced the IA8-ARCaP and LNCaP/HIF-1a viable cell number in a dose-dependent manner (with increasing concentrations from 15 to 75 micromol/L). Less than 15 micromol/L genistein was selected as the low dose concentration, which did not affect cell proliferation. The treatment of cells with low-dose genistein induced the reversal of EMT, which was confirmed by cell morphological transition and the expression changes of EMT-related markers. The reversal of EMT in the PCa cells by low-dose genistein was in a dose-dependent manner. Moreover, low-dose genistein effectively inhibited invasion of the PCa cells in vitro. CONCLUSION: These results showed that treatment with low-dose genistein may be a potential strategy for the suppression of invasive growth through the reversal of EMT in cancer cells, which justifies the potential use of soybean foods as a practical chemopreventive approach for patients with PCa.
Assuntos
Anticarcinógenos/farmacologia , Células Epiteliais/efeitos dos fármacos , Genisteína/farmacologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/prevenção & controle , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Invasividade Neoplásica/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sais de Tetrazólio , TiazóisRESUMO
OBJECTIVE: To determine the effect of the transforming growth factor beta (TGF-beta) on the expression of invasion and metastasis associated proteins in the prostate cancer LNCaP cell line in vitro. METHODS: The prostate cancer cell line LNCaP was treated with TGF-beta in vitro. Western blotting was used to detect the expression of the "invasion and metastasis" associated proteins E-Cadherin, N-Cadherin and Vimentin. RESULTS: The expression of N-Cadherin and Vimentin of the LNCaP cells treated with TGF-beta for 12 hours was significantly upregulated, but not that of E-Cadherin. CONCLUSION: TGF-beta may induce epithelial-mesenchymal transition (EMT) of LNCaP cells which might be of importance in promoting prostate cancer cells invading to ambient tissues and metastasizing to distant organs.
Assuntos
Fator de Crescimento Transformador beta/farmacologia , Western Blotting , Caderinas/biossíntese , Linhagem Celular Tumoral , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Regulação para Cima/efeitos dos fármacos , Vimentina/biossínteseRESUMO
Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen (PSA) level ≥50% during the treatment and investigated the potential role of time to nadir (TTN) of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS). In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN <17 weeks (42.83 vs 21.50 weeks, P < 0.001). The time to PSA progression in patients with TTN ≥17 weeks was 11.44 weeks compared to 5.63 weeks when TTN was <17 weeks. We found several factors to be associated with OS, including TTN (hazard ratio [HR]: 3.937, 95% confidence interval [CI]: 1.502-10.309, P = 0.005), PSA level at the diagnosis of cancer (HR: 4.337, 95% CI: 1.616-11.645, P = 0.004), duration of initial androgen deprivation therapy (HR: 2.982, 95% CI: 1.104-8.045, P = 0.031), neutrophil-to-lymphocyte ratio (HR: 3.963, 95% CI: 1.380-11.384, P = 0.011), and total PSA response (Class 1 [<0 response] compared to Class 2 [0-50% response], HR: 3.978, 95% CI: 1.278-12.387, P = 0.017). In conclusion, TTN of PSA remains an important prognostic marker in predicting therapeutic outcome in Chinese population who receive chemotherapy for mCRPC and have >50% PSA remission.
Assuntos
Antineoplásicos/uso terapêutico , Docetaxel/uso terapêutico , Calicreínas/sangue , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , China , Humanos , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neutrófilos , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
OBJECTIVE: To evaluate the potential role of neutrophil-to-lymphocyte ratio (NLR) with therapeutic response in patients who were treated with docetaxel for mCRPC. MATERIALS AND METHODS: We retrospectively analyzed the clinical data from 111 consecutive patients who were treated with docetaxel for mCRPC from 2009 to 2016 in a single center from Northwestern China. Pretreatment baseline and follow-up data including age, PSA response, Gleason score, and cycle number were reviewed, and multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS) and progression-free survival (PFS). RESULTS: In Kaplan-Meier analyses, the NLR (optimal threshold 3.3), total PSA response, number of chemotherapy cycles, stage T, baseline of PSA, albumin, presence of visceral metastases, and PSA level at the diagnosis of cancer were significantly associated with OS, respectively. In multivariable analyses, higher NLR (>3.3), PSA level at the diagnosis of cancer (≥162 ng/ml), number of chemotherapy cycles, and albumin (<40.5 g/l) were associated with increased risk of death, respectively. Meanwhile, young age, higher NLR, number of chemotherapy cycles, presence of visceral metastases, and poor PSA response were associated with shorter PFS. CONCLUSION: NLR combined with PSA level at the diagnosis of cancer remains an important prognostic marker in predicting therapeutic outcome in Chinese men who receive chemotherapy for mCRPC.
Assuntos
Adenocarcinoma/sangue , Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neutrófilos , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , China , Intervalo Livre de Doença , Docetaxel , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Prognóstico , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Albumina Sérica/metabolismo , Taxa de Sobrevida , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
We have recently reported tumor suppressive role of DAB2IP in RCC development. In this study, We identified one CpG methylation biomarker (DAB2IP CpG1) located UTSS of DAB2IP that was associated with poor overall survival in a cohort of 318 ccRCC patients from the Cancer Genome Atlas (TCGA). We further validated the prognostic accuracy of DAB2IP CpG methylation by pyrosequencing quantitative methylation assay in 224 ccRCC patients from multiple Chinese centers (MCHC set), and 239 patients from University of Texas Southwestern Medical Center at Dallas (UTSW set) by using FFPE samples. DAB2IP CpG1 can predict the overall survival of patients in TCGA, MCHC, and UTSW sets independent of patient age, Fuhrman grade and TNM stage (all p<0.05). DAB2IP CpG1 successfully categorized patients into high-risk and low-risk groups with significant differences of clinical outcome in respective clinical subsets, regardless of age, sex, grade, stage, or race (HR: 1.63-7.83; all p<0.05). The detection of DAB2IP CpG1 methylation was minimally affected by ITH in ccRCC. DAB2IP mRNA expression was regulated by DNA methylation in vitro. DAB2IP CpG1 methylation is a practical and repeatable biomarker for ccRCC, which can provide prognostic value that complements the current staging system.
Assuntos
Carcinoma de Células Renais/genética , Metilação de DNA , Neoplasias Renais/genética , Proteínas Ativadoras de ras GTPase/genética , Biomarcadores Tumorais/genética , Ilhas de CpG/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Estadiamento de Neoplasias , PrognósticoRESUMO
This paper proposes a region sampling based autofocus method for rapid and robust autofocus in microscope. Image content and region size are considered in region sampling criteria. An intelligent search algorithm which employs quartering hill climbing search and golden section search is developed, in which rule-based evaluation of sampled focusing regions is applied. Experimental results demonstrate that the proposed method can significantly improve the performance of image-based autofocus.
RESUMO
Clear cell renal cell carcinomas (ccRCCs) display divergent clinical behaviours. Molecular markers might improve risk stratification of ccRCC. Here we use, based on genome-wide CpG methylation profiling, a LASSO model to develop a five-CpG-based assay for ccRCC prognosis that can be used with formalin-fixed paraffin-embedded specimens. The five-CpG-based classifier was validated in three independent sets from China, United States and the Cancer Genome Atlas data set. The classifier predicts the overall survival of ccRCC patients (hazard ratio=2.96-4.82; P=3.9 × 10(-6)-2.2 × 10(-9)), independent of standard clinical prognostic factors. The five-CpG-based classifier successfully categorizes patients into high-risk and low-risk groups, with significant differences of clinical outcome in respective clinical stages and individual 'stage, size, grade and necrosis' scores. Moreover, methylation at the five CpGs correlates with expression of five genes: PITX1, FOXE3, TWF2, EHBP1L1 and RIN1. Our five-CpG-based classifier is a practical and reliable prognostic tool for ccRCC that can add prognostic value to the staging system.
Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Metilação de DNA , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de SobrevidaRESUMO
Androgen therapy is the mainstay of treatment for the hypogonadotropic hypogonadal micropenis because it obviously enhances penis growth in prepubescent microphallic patients. However, the molecular mechanisms of androgen treatment leading to penis growth are still largely unknown. To clarify this well-known phenomenon, we successfully generated a castrated male Sprague Dawley rat model at puberty followed by testosterone administration. Interestingly, compared with the control group, testosterone treatment stimulated a dose-dependent increase of penis weight, length, and width in castrated rats accompanied with a dramatic recovery of the pathological changes of the penis. Mechanistically, testosterone administration substantially increased the expression of androgen receptor (AR) protein. Increased AR protein in the penis could subsequently initiate transcription of its target genes, including keratin 33B (Krt33b). Importantly, we demonstrated that KRT33B is generally expressed in the rat penis and that most KRT33B expression is cytoplasmic. Furthermore, AR could directly modulate its expression by binding to a putative androgen response element sequence of the Krt33b promoter. Overall, this study reveals a novel mechanism facilitating penis growth after testosterone treatment in precastrated prepubescent animals, in which androgen enhances the expression of AR protein as well as its target genes, such as Krt33b.
Assuntos
Queratinas/metabolismo , Pênis/crescimento & desenvolvimento , Receptores Androgênicos/metabolismo , Transdução de Sinais , Testosterona/fisiologia , Animais , Sequência de Bases , Primers do DNA , Masculino , Pênis/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
This study aimed to investigate the correlations among androgen receptor (AR) CAG repeat polymorphism, sex hormones and penile length in healthy Chinese young adult men. Two hundred and fifty-three healthy men (aged 22.8 ± 3.1 years) were enrolled. The individuals were grouped as CAG short (CAG S ) if they harbored repeat length of ≤ 20 or as CAG long (CAG L ) if their CAG repeat length was >20. Body height/weight, penile length and other parameters were examined and recorded by the specified physicians; CAG repeat polymorphism was determined by the polymerase chain reaction (PCR) method; and the serum levels of the sex hormones were detected by radioimmunoassay. Student's t-test or linear regression analysis was used to assess the associations among AR CAG repeat polymorphism, sex hormones and penile length. This investigation showed that the serum total testosterone (T) level was positively associated with the AR CAG repeat length (P = 0.01); whereas, no significant correlation of T or AR CAG repeat polymorphism with the penile length was found (P = 0.593). Interestingly, an inverse association was observed between serum prolactin (PRL) levels and penile length by linear regression analyses (ß= -0.024, P = 0.039, 95% confidence interval (CI): -0.047, 0). Collectively, this study provides the first evidence that serum PRL, but not T or AR CAG repeat polymorphism, is correlated with penile length in the Han adult population from northwestern China.