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1.
Cancer Sci ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31967368

RESUMO

p62 is associated with 2 major cellular defense mechanisms against metabolic and oxidative stress, autophagy and the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor-E2-related factor 2 (NRF2) system. Recent studies indicate that the p62-KEAP1-NRF2 pathway promotes tumorigenesis and tumor growth mediated by NRF2-dependent antioxidative response. However, whether p62 is involved in bladder cancer (BCa) development remains unknown. Here, we found that p62 is overexpressed in BCa tissue and several BCa cell lines. The knockdown of p62 inhibits BCa cell growth both in vitro and in vivo, with increased intracellular reactive oxygen species level. Mechanically, p62 activates NRF2 signaling by sequestrating KEAP1, which leads to the upregulation of antioxidant genes (Gclc, Gstm5, and Gpx2), thus protecting BCa cells from oxidative stress. Our findings indicate that p62 might be involved in the development of BCa and serve as a potential therapeutic target.

2.
Urol Oncol ; 38(1): 2.e11-2.e17, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31672485

RESUMO

OBJECTIVE: Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China. We have previously shown that time to nadir (TTN) of prostate-specific antigen (PSA) is an important prognostic factor in patients from a single center in Northwestern China. In this study, we performed a multicenter validation of the prognostic role of TTN in additional Chinese patients with mCRPC receiving docetaxel treatment. MATERIALS AND METHODS: The data were gathered from 170 eligible Chinese patients who received docetaxel chemotherapy from January 2007 to October 2018 in 11 Chinese Prostate Cancer Consortium member hospitals in China. 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) and progression-free survival (PFS). RESULTS: Patients with a TTN ≥ 15 weeks had a longer OS and PFS compared to those with a TTN < 15 weeks (43 vs. 15 months, P < 0.001; 24 vs. 6 months, P < 0.001, respectively). In addition, Patients with a TTN ≥ 15 weeks and PSA nadir <4.55ng/ml were associated with longer OS than others (HR 0.093, 95% CI 0.044-0.188, P < 0.001; HR 4.002, 95% CI 1.890-8.856, P = 0.001, respectively) and TTN, PSA nadir, PSA baseline (optimal threshold 56.07 ng/ml), and PSA reduction (optimal threshold 50%) were associated with PFS (HR 0.238, 95% CI 0.149-0.382, P < 0.001; HR 1.676, 95% CI 1.033-2.722, P = 0.037; HR 1.770, 95% CI 1.134-2.763, P = 0.012; HR 0.573, 95% CI 0.428-0.756, P < 0.001; respectively). Furthermore, patients with a PSA nadir <4.55 ng/ml had longer OS and PFS compared to other patients when TTN was ≥15 weeks. CONCLUSION: In this multicenter validation study, TTN and PSA nadir remain important prognostic markers in predicting therapeutic outcomes in Chinese men who receive chemotherapy for mCRPC.

4.
Medicine (Baltimore) ; 98(48): e18000, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770212

RESUMO

RATIONALE: Bladder cancer (BC) is commonly diagnosed in the urinary system and the most common subtype is transitional urothelial carcinoma (TCC). Even with the best treatment, tumor recurrence and metastases always occur. While clinicians commonly observe the metastases to pelvic lymph nodes, liver, lung, and bone, it may infrequently spread to some uncommon locations. PATIENT CONCERNS: The patient was a 67-year-old man with a diagnosis of high-grade TCC with squamous differentiation in the bladder and prostate. Subsequently, radical cystoprostatectomy, adjuvant radiotherapy, and chemotherapy were performed. However, he felt intermittent right scrotal pain about 1 year later. DIAGNOSIS: Ultrasound strongly suggested a testicular neoplasm of right testis, but the left was normal. INTERVENTIONS: The patient underwent a right radical orchiectomy and histopathology confirmed testicular metastatic neoplasm from bladder. Moreover, further examination with positron emission tomography revealed no visible distant spread of the urothelial carcinoma. OUTCOMES: No signs of tumor recurrence or distant metastasis were visible under follow-up 1 year after radical orchiectomy. LESSONS: Testicular mass may be metastatic tumor during follow-up for patients who were diagnosed as BC, especially for TCC with variant histology. The reason of this could be explained of residual micrometastases after surgery and need more examination to discover local micrometastases to apply more aggressive treatment.


Assuntos
Carcinoma de Células de Transição/secundário , Cistectomia/efeitos adversos , Prostatectomia/efeitos adversos , Neoplasias da Próstata/patologia , Neoplasias Testiculares/secundário , Neoplasias da Bexiga Urinária/patologia , Idoso , Carcinoma de Células de Transição/cirurgia , Cistectomia/métodos , Humanos , Masculino , Período Pós-Operatório , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Neoplasias da Bexiga Urinária/cirurgia , Urotélio/patologia
5.
Cell Death Dis ; 10(6): 437, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164632

RESUMO

The prognosis of bladder cancer (BCa) depends on several key factors including anatomical site, tumor grade, and stage. In general, muscle-invasive bladder cancer (MIBC) is associated with higher incidence of distant metastasis compared with Non-muscle-invasive bladder cancer (NMIBC). Treatment outcome of the patients with metastatic BCa has been very poor with ~15% of overall survival rate. Thus, it is apparently important to understand the underlying biology for metastatic progression of BCa. Although epithelial-mesenchymal transition (EMT) has long been implicated in BCa metastasis and treatment resistance, the underlying mechanism is not fully understood. In this study, we have identified that the expression of interferon induced protein with tetratricopeptide repeats 5 (IFIT5) is positively correlated with pathological characteristics, and predicts a poor prognosis of BCa patients. Since the function of IFIT5 in BCa has not yet been characterized, we demonstrate that IFIT5 can induce EMT, promote cell migration and invasion, and increase the expression of ICAM1 in BCa via down-regulation of mature miR-99a. Moreover, ICAM1 is shown as a direct target of miR-99a. Overall, we conclude that IFIT5 is a new oncogene in BCa.

6.
Photobiomodul Photomed Laser Surg ; 37(1): 25-30, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31050941

RESUMO

Objective: Our study aimed to detect whether 450 nm blue laser can be applied effectively and safely in endosocopic submucosal dissection (ESD) system for surgery in colonic tissue. Background data: Semiconductor blue laser has been applied in surgery due to its excellent cutting property, however, whether blue laser can be applied in colonic surgery has not been reported. Materials and methods: Porcine colon tissues were vaporized by 450 nm blue semiconductor laser at 10-25 W and at working distances from 0.5 to 3 mm, with a three-dimensional scanning system. Moreover, we designed an ESD model and applied blue laser at 10 W on porcine colonic tissues with this system. Dimensions of the vaporized tissues and coagulation zones were assessed under microscopy. Results: Since the thickness of colonic wall is no more than 1 mm, first we determined the cutting property and safety of blue laser on porcine colon tissue and found that blue laser at 10 W made lesions shallower than 1 mm and the depth of vaporization can be controlled effectively within muscularis mucosa and submucosa. Moreover, a large scale of porcine colonic tissue was vaporized precisely by blue laser at power of 10 W with the ESD system ex vivo. Conclusions: Our results indicate that 450 nm blue laser at 10 W can be well controlled for laser-tissue interaction with excellent cutting efficiency and less thermal damage in adjacent tissues especially side of the submucosa. Therefore, 450 nm semiconductor blue laser could be a safe alternative approach for colonic surgery.

7.
Clin Cancer Res ; 25(14): 4542-4551, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31000589

RESUMO

PURPOSE: Renal cell carcinoma (RCC) is known to be highly radioresistant but the mechanisms associated with radioresistance have remained elusive. We found DOC-2/DAB2 interactive protein (DAB2IP) frequently downregulated in RCC, is associated with radioresistance. In this study, we investigated the underlying mechanism regulating radioresistance by DAB2IP and developed appropriate treatment. EXPERIMENTAL DESIGN: Several RCC lines with or without DAB2IP expression were irradiated with ionizing radiation (IR) for determining their radiosensitivities based on colony formation assay. To investigate the underlying regulatory mechanism of DAB2IP, immunoprecipitation-mass spectrometry was performed to identify DAB2IP-interactive proteins. PARP-1 expression and enzymatic activity were determined using qRT-PCR, Western blot analysis, and ELISA. In vivo ubiquitination assay was used to test PARP-1 degradation. Furthermore, in vivo mice xenograft model and patient-derived xenograft (PDX) model were used to determine the effect of combination therapy to sensitizing tumors to IR. RESULTS: We notice that DAB2IP-deficient RCC cells acquire IR-resistance. Mechanistically, DAB2IP can form a complex with PARP-1 and E3 ligases that is responsible for degrading PARP-1. Indeed, elevated PARP-1 levels are associated with the IR resistance in RCC cells. Furthermore, PARP-1 inhibitor can enhance the IR response of either RCC xenograft model or PDX model. CONCLUSIONS: In this study, we unveil that loss of DAB2IP resulted in elevated PARP-1 protein is associated with IR-resistance in RCC. These results provide a new targeting strategy to improve the efficacy of radiotherapy of RCC.

8.
World J Urol ; 37(12): 2671-2675, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30843089

RESUMO

PURPOSE: To describe a green-laser marking technique to assist partial cystectomy, which allows accurate identification of tumour margins, and provide our initial experience with ten patients. METHODS: Between January 2014 and February 2018, ten patients suspected with muscle-invasive bladder cancer and request of bladder-preserving treatment were selected. In each case, bilateral pelvic lymphadenectomy was performed before green-laser assisted laparoscopic partial cystectomy. Under the direct view of cystoscope, the front-firing green-laser incision was performed 0.5-1 cm away from the exterior margin of lesion with adequate depth into the fat tissue. Tumours were then en bloc removed via laparoscope under the tracing of laser beam. RESULTS: The location of 12 tumours in 10 patients was superior wall in 7 cases, lateral wall in 3 cases, anterior wall in 1 case, and posterior wall in 1 case. All procedures were completed without serious complications. The median operating time was 270 (210-360) min with a median haemoglobin decrease of 11 (3-38) g/L. Nine patients were high-grade transitional cell carcinoma and one patient was urachal carcinoma, and the clinical stage was pT1 in 1 case, pT2 in 4 cases, and pT3 in 5 cases. The pathological evaluation of tumour margins was negative in 10 patients. During the follow-up, no recurrence or metastasis were detected in 8 patients, but 2 patients presented regional recurrence. CONCLUSION: The use of green-laser marking technique during laparoscopic partial cystectomy is a feasible manoeuvre in assisting the accurate incision and minimizing injury to the remaining bladder.

9.
World J Urol ; 37(12): 2677-2682, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30830276

RESUMO

PURPOSE: The T1 substage, according to the relationship between muscularis mucosae (MM) and tumors, is a promising prognostic factor for T1 bladder cancer. However, the identification rate of MM is low in specimens, and it is, therefore, not widely used in clinical practice. In this study, we investigated whether en bloc resection of non-muscle invasive bladder cancer (NMIBC) could improve the identification of muscularis mucosae (MM), which may further accurate identification of the T1 substage. PATIENTS AND METHODS: Specimens from 158 patients with primary NMIBC were retrospectively reviewed by two independent pathologists to assess the presence of MM and stratify the T1 substage. Of 158 specimens, 70 specimens were obtained via TURBt with a plasma kinetic loop and 88 were obtained via front-firing potassium-titanyl-phosphate (KTP) green-light laser en bloc resection. Univariable and multivariable logistic regression models were used to analyze the relationship between the clinical characteristics and the presence of MM. RESULTS: The mean age was 58.22 years (range 18-85 years). Multivariable logistic regression analysis showed that the KTP laser resection method was associated with the presence of MM in specimens (P = 0.008). In addition, tumors with smaller sizes, which could also be en bloc resected with TURBt (e.g., ≤1 cm), had a higher presence of MM (P = 0.047). CONCLUSIONS: En bloc resection improves the identification rate of MM, which may enhance the accurate identification of the T1 substage.

10.
Lasers Med Sci ; 34(4): 807-813, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30406852

RESUMO

Low-power blue laser allows clean cutting with little bleeding and no undesired coagulations in adjacent tissues; however, studies on high-power blue laser soft tissue ablation properties, including vaporization and coagulation, have not been reported yet. The purpose of this study is to evaluate and analyze the ablation efficacy and coagulation properties of bladder epithelium tissues with a 30-W 450-nm wavelength blue laser. Well-designed ex vivo experiments compared blue laser and 532-nm LBO green laser, both with laser power up to 30 W, for porcine bladder tissue vaporization and coagulation at different experimental parameter settings. At working distance of 1 mm and sweeping speed of 1.5 mm/s, the vaporization efficiency of blue laser and green laser was 5.14mm3/s and 1.20mm3/s, while the depth of coagulation layer was 460 ± 70 µm and 470 ± 80 µm, respectively. We found both blue laser and green laser have excellent efficacy of tissue vaporization and similar tissue coagulation properties. Moreover, in a set of in vivo experiments simulated laser transurethral resection (TUR) surgery on dogs, we found both blue laser and green laser exhibited similar and satisfactory vaporization and coagulation outcomes. Taken together, our results demonstrate that a 450-nm wavelength high-power diode blue laser, like 532-nm wavelength green laser, is capable to produce high efficient tissue vaporization, low-laser tissue penetration, good tissue coagulation, and has low thermal damage to adjacent tissues. Therefore, a 30-W blue diode laser could be a new and safe alternative for surgeries of superficial bladder diseases.


Assuntos
Terapia a Laser , Lasers Semicondutores , Bexiga Urinária/efeitos da radiação , Bexiga Urinária/cirurgia , Animais , Cães , Fotocoagulação a Laser , Masculino , Suínos
11.
J Cell Physiol ; 234(3): 2741-2755, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30145816

RESUMO

Bladder cancer, the second most common genitourinary malignancy, severely endangers the human health. Rising evidence suggests that metabotropic glutamate receptors (mGluRs) are involve in tumor progression. In this study, we observed that metabotropic glutamate receptor 4 (mGluR4) was functionally expressed in normal and cancerous bladder cells and its expression was positively correlated with high bladder cancer grading. We further confirmed that the activation of mGluR4 by VU0155041, an mGluR4-specific agonist, decreased cyclic adenosine monophosphate (cAMP) concentration and cell viability, promoted apoptosis and inhibited proliferation in bladder cancer cells, whereas MSOP (group III mGluR antagonist) or mGluR4 knockdown eliminated the effects of mGluR4 activity. Western blotting revealed the decreased cyclin D1 expression, increased procaspase-8/9/3 cleavage, and unbalanced Bcl-2/Bax expression in bladder cancer cell lines after mGluR4 activation, and likewise MSOP and mGluR4 knockdown abrogated the actions of mGluR4 activity. In vivo study showed that mGluR4 activation significantly inhibited tumor growth of bladder cancer via suppressing proliferation and promoting apoptosis. Furthermore, upregulation of phosphatase and tensin homolog (PTEN) and inhibition of Akt phosphorylation were also observed after mGluR4 activation. Similar with VU0155041, the Akt-specific inhibitor markedly promoted apoptosis and inhibited proliferation. Nevertheless, the PTEN-specific inhibitor significantly abolished the mGluR4 activation-induced cell apoptosis and proliferative inhibition in bladder cancer cell lines. These results indicate that mGluR4 can regulate the switch between survival and death via the cAMP/PTEN/AKT signaling pathway in bladder cancer cells. Our findings suggest that mGluR4 has diagnostic and prognostic potential for bladder cancer, and the development of mGluR4 agonist may be a promising strategy for bladder cancer treatment.


Assuntos
Apoptose , Receptores de Glutamato Metabotrópico/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Anilidas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ácidos Cicloexanocarboxílicos/farmacologia , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico
12.
Oncol Rep ; 40(5): 2836-2843, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30226607

RESUMO

Despite the availability of a number of treatment options, certain cases of primary prostate cancer (PCa) will develop into metastatic PCa, in which epithelial­mesenchymal transition (EMT) serves an important role. Recently, a natural flavonoid known as 2'­hydroxyflavanone (2HF) exerts remarkable anticancer activity on various types of cancer. Our previous study demonstrated that 2HF could promote apoptosis and inhibit the proliferation of PCa cells, but whether 2HF is involved in the regulation of EMT, and cell migration and invasion in metastatic PCa remains unknown. The present study used two different metastatic PCa cell lines (PC­3 and DU145) to investigate the effects of 2HF on EMT, and cell migration and invasion. The results demonstrated that 2HF could inhibit EMT, and cell migration and invasion through the Wnt/ß­catenin signaling pathway by suppressing GSK­3ß phosphorylation, ß­catenin expression and transactivation. In conclusion, the present study revealed a novel function of 2HF, which may be used to prevent or treat PCa metastasis.


Assuntos
Flavanonas/farmacologia , Glicogênio Sintase Quinase 3 beta/genética , Neoplasias da Próstata/tratamento farmacológico , beta Catenina/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Via de Sinalização Wnt/efeitos dos fármacos
13.
Cell Death Dis ; 9(9): 881, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158581

RESUMO

Patients with renal cell carcinoma (RCC) often develop resistance to antivascular drugs and eventually succumb to disease. However, the underlying molecular mechanism remains poorly understood. In this study, we demonstrated that RASAL2, a RAS GTPase-activating protein, played a tumor-suppressive role in RCC by targeting tumor angiogenesis. Firstly, we showed that RASAL2 was frequently epigenetically silenced in RCC, and its loss was negatively correlated with overall survival of RCC patients. Furthermore, we discovered that RASAL2 could inhibit RCC angiogenesis in vitro and in vivo. Mechanistically, we identified that RASAL2 could activate GSK3ß by reducing Ser9 phosphorylation and subsequently decrease the expression of c-FOS and vascular endothelial growth factor A (VEGFA). Interruption of the p-GSK3ß/c-FOS pathway with the specific inhibitor or small interfering RNA could reverse the expression of VEGFA, which may provide a new insight to prevent RCC from resistance to antivascular therapy.


Assuntos
Carcinoma de Células Renais/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias Renais/metabolismo , Neovascularização Patológica/metabolismo , Animais , Carcinoma de Células Renais/patologia , Linhagem Celular , Linhagem Celular Tumoral , Epigênese Genética/fisiologia , Proteínas Ativadoras de GTPase/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/patologia , Fosforilação/fisiologia , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Urol Oncol ; 36(10): 472.e11-472.e20, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30139661

RESUMO

BACKGROUND: AKR1C3, as a crucial androgenic enzyme, facilitates intratumoral androgen biosynthesis and androgen receptor activation in castration-resistant prostate cancer (PCa). The data has shown that AKR1C3 expression is significantly elevated in clinical metastatic PCa specimens, indicating a potential role of AKR1C3 in PCa metastasis. METHODS: C4-2, 22RV1-T, and PC-3 cells with higher AKR1C3 expression were selected and treated with several specific AKR1C3 shRNAs or small molecule inhibitor, and the cell migration and invasion abilities were detected by wound healing assay and Transwell assay. The expression of several epithelial-mesenchymal transition (EMT) markers (i.e., E-cadherin and vimentin) and the related transcription factors (i.e., ZEB1, TWIST1, and SLUG) was examined by Western blot or quantitative PCR assays, and the phosphorylation of AKT or ERK was detected by Western blot. Also, subcutaneous xenografts with 22RV1-T sublines were used to detect in vivo tumor growth, and the expression of E-cadherin, vimentin, and ZEB1 by immunohistochemical staining. The correlation between AKR1C3 and EMT marker expression in clinical specimens was analyzed. RESULTS: AKR1C3 was overexpressed in more aggressive PCa cell lines regardless of the androgen receptor status. Knockdown of AKR1C3 expression or inhibition of AKR1C3 activity could significantly suppress cell migration and invasion abilities in vitro, and increase E-cadherin expression but decrease vimentin expression, in which the phosphorylation of ERK and the EMT-associated transcription factor expression were specifically down-regulated. Also, knockdown of AKR1C3 could suppress PCa tumorigenesis and reverse EMT in vivo. Moreover, there was a significant correlation between AKR1C3 expression and EMT in human PCa specimens from public tissue microarray. CONCLUSIONS: AKR1C3 is a novel EMT driver in PCa metastasis through activating ERK signaling.


Assuntos
Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias da Próstata/patologia , Animais , Biomarcadores Tumorais/análise , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia
15.
Cell Signal ; 48: 38-44, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29702203

RESUMO

Muscle-invasive or metastatic bladder cancer (BCa) is a life-threatening disease for patients, and tumor angiogenesis is believed to play a critical role in the progression of BCa. However, its underlying mechanism of tumor angiogenesis is still poorly understood. In this study, we discovered that RASAL2, a RAS GTPase activating protein, could inhibit BCa angiogenesis based on our shRNA/siRNA knockdown or ectopic cDNA expression experiments. Mechanistically, RASAL2 downregulation could enhance the phosphorylation of AKT and then subsequently upregulate the expression of ETS1 and VEGFA. Furthermore, there was a negative correlation between RASAL2 and VEGFA or CD31 expression in subcutaneous xenograft and human BCa specimens. Taken together, we provide a new insight into the molecular mechanism of BCa progression, in which RASAL2 can be a new therapeutic target.


Assuntos
Proteínas de Transporte/fisiologia , Neovascularização Patológica/fisiopatologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Bexiga Urinária/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Neovascularização Patológica/genética , Transdução de Sinais , Neoplasias da Bexiga Urinária/patologia
16.
J Biomed Nanotechnol ; 14(1): 161-167, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29463373

RESUMO

OBJECTIVE: As a novel cell-permeable peptide, polyarginine (R11) showed great potential as contrast agent to target bladder cancer (BCa) for therapeutic applications. However, its diagnostic ability and uptake efficiency between BCa and normal bladder tissues is unknown. In this study, we investigated the feasibility of R11 conjugated with fluorescein isothiocyanate (FITC-R11) for detecting BCa in clinical practice. METHOD: FITC-R11 was synthesized and incubated with BCa cell lines (T24, 5637, RT4), normal immortalized human bladder epithelial cell line (SVHUC) and clinical specimens from BCa and benign prostate hyperplasia patients. The uptake efficiency was determined by the mean values of relative FITC intensity. Furthermore, FITC-R11 was intravesically injected into the athymic nude mice bearing orthotopic T24-t tumors and pulmonary metastasis of bladder tumor mice models, the fluorescence intensity of bladder tumors and normal bladder tissues was examined, as well as lung tissues. RESULT: After incubation with FITC-R11, the fluorescence intensity of T24, 5637, RT4 and SVHUC cell line was 64678.56 ± 9699.27, 46456.22 ± 2588.06, 33802.02 ± 429.72 and 17785.01 ± 1704.36, respectively (P < 0.05). In the athymic nude mice bearing orthotopic T24-t tumors, FITC-R11 showed elevated accumulation in the bladder tumors compared with normal bladder tissues, FITC-R11 was also accumulated in the lung of pulmonary metastasis mice. Moreover, the uptake efficiency of FITC-R11 in patients' BCa tissues was much higher than in normal bladder tissues (6441.95 vs. 1196.92, P < 0.05), as well as the urine samples of BCa patients and benign prostate hyperplasia patients (30250.37 vs. 4948.42, P < 0.05). CONCLUSION: As compared with normal bladder tissue, FITC-R11 is a more specific molecular probe for BCa, and has the potential application in clinical practice.


Assuntos
Peptídeos Penetradores de Células , Oligopeptídeos , Neoplasias da Bexiga Urinária/diagnóstico , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Nus , Células Tumorais Cultivadas
17.
Oncol Lett ; 15(3): 3482-3489, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29467870

RESUMO

Lung is one of the most common sites for bladder cancer to metastasize. Although the involvement of the epithelial-to-mesenchymal transition (EMT) in bladder cancer progression has been established, the mechanism of EMT induction remains unclear. In order to investigate this, T24-parental (P) and T24-lung (L) bladder cancer cells were obtained from primary tumors and lung metastatic sites of an animal model with orthotopic spontaneous metastatic bladder cancer, according to a protocol previously described. Compared with T24-P cells, mesenchymal-like T24-L cells exhibited an increased ability in tumor invasion and metastasis, as well as an increased expression of hypoxia-inducible factor (HIF)-1α, zinc finger E-box-binding homeobox 1 (ZEB1), vimentin and N-cadherin and lower level of cytokeratin 18 were observed. Mechanistically, it was identified that HIF-1α increases ZEB1 expression and subsequently regulates the expression of EMT-related genes in both HIF-1α knocking down by siRNA and gain-in HIF-1α by hypoxia culture cell models. In addition, the expression of HIF-1α and ZEB1 in bladder cancer tissues were increased compared with normal bladder epithelial tissues, as well as significantly increased in the high-grade, invasive and metastatic bladder cancer tissues compared with low-grade, superficial and non-metastatic bladder cancer tissues by using immune-histochemical staining assay. Notably, the protein level of HIF-1α was positively associated with that of ZEB1 in bladder cancer tissues. Results from the present study indicate that HIF-1α promotes ZEB1 expression and EMT in the T24-L human bladder cancer lung metastasis animal model, suggesting that HIF-1α serves an important function in the metastasis of bladder cancer, and HIF-1α and ZEB1 may be potential targets for inhibiting bladder metastasis in the future.

18.
Asian J Androl ; 20(2): 173-177, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28905815

RESUMO

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 Tempo
19.
Int J Cancer ; 141(10): 2121-2130, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28722220

RESUMO

The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration-resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed that a novel class of agents (thailanstatins, TSTs and spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3' splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application.


Assuntos
Apoptose/efeitos dos fármacos , Variação Genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Piranos/farmacologia , Processamento de RNA/genética , Receptores Androgênicos/genética , Burkholderia/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/patologia , Isoformas de Proteínas , Receptores Androgênicos/química , Células Tumorais Cultivadas
20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 33(5): 668-676, 2017 May.
Artigo em Chinês | MEDLINE | ID: mdl-28502307

RESUMO

Objective To study the expression of DAB2 interacting protein (DAB2IP) in human bladder cancer tissues and analyze its relationship with pathological grade and clinical stage, and observe its role in drug resistance of bladder cancer cells. Methods The expression of DAB2IP in primary and recurrent bladder cancers was detected by immunohistochemical staining. RNA interference (RNAi) technique was used to down-regulate the expression of DAB2IP in 5637 and 253J bladder cancer cells. MTT assay and clone formation assay were performed to test the sensitivity of cancer cells to pirarubicin. Flow cytometry was done to detect the apoptosis rate of low-DAB2IP-expressing cells treated with pirarubicin. Results The expression of DAB2IP was negatively correlated with TNM stage, pathological grade and lymph node metastasis of bladder cancer. The expression of DAB2IP in the recurrent bladder cancer was lower than that in the primary bladder cancer. The low expression of DAB2IP in bladder carcinoma cells was related to drug resistance. Knock-down of DAB2IP enhanced the colony formation of bladder cancer cells, reduced the expressions of PARP and caspase-3, increased expressions of Bcl-2 and Mcl-1, reduced the apoptosis of cancer cells and induced chemotherapy tolerance. Conclusion Knock-down of DAB2IP can promote the proliferation and inhibit the apoptosis of bladder cancer cells, and increase the resistance to chemotherapy.


Assuntos
Apoptose/genética , Proliferação de Células/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Proteínas Ativadoras de ras GTPase/genética , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes/métodos , Humanos , Masculino , Pessoa de Meia-Idade
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