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1.
J Korean Med Sci ; 35(5): e31, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32030920

RESUMO

BACKGROUND: Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated. METHODS: We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases. RESULTS: TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort. CONCLUSION: TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais , Inibidores de Proteínas Quinases , Receptores Tipo I de Fatores de Necrose Tumoral , Transdução de Sinais , Fator de Necrose Tumoral alfa , Adulto , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/diagnóstico , Neoplasias Renais/metabolismo , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Análise de Sobrevida , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
2.
Life Sci ; 243: 117230, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923422

RESUMO

AIMS: Accumulating evidence has confirmed the involvement of the homeobox (HOX) gene family in carcinogenesis. HOXC11, belongs to the homeobox-C (HOXC) gene cluster, has been reported to play important roles in the development of several cancers. However, its expression and clinical value in pan-cancer remain elusive. MATERIALS AND METHODS: Bioinformatics analysis, CCK-8 assay, Flow cytometry and Western blot were used to analyze gene expression and patient survival, cell proliferation, cell apoptosis and protein level, respectively. KEY FINDINGS: In this study, we comprehensively analyzed the expression profile and prognostic value of HOXC11 in human pan-cancer using online The Cancer Genome Atlas (TCGA) databases. HOXC11 was widely up-regulated in tumor tissues when compared with the normal tissues in pan-cancer across nine cancer types. In addition, high mRNA level of HOXC11 predicted poor overall survival (OS) of patients with adrenocortical carcinoma (ACC), colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), mesothelioma (MESO) and pancreatic adenocarcinoma (PAAD), respectively. By comparative analysis, we found that HOXC11 was up-regulated and closely correlated patient OS in COAD and KIRC. Functionally, down-regulation of HOXC11 inhibited cell proliferation but promoted apoptosis of COAD and KIRC in vitro. Mechanistically, HOXC11 promoted cell proliferation of COAD and KIRC might by inactivating the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. SIGNIFICANCE: Our findings suggest that HOXC11 may act as a tumor driving gene in COAD and KIRC.


Assuntos
Adenocarcinoma/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias do Colo/metabolismo , Proteínas de Homeodomínio/fisiologia , Neoplasias Renais/metabolismo , Oncogenes , Adenocarcinoma/patologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/patologia , Regulação para Baixo/fisiologia , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Renais/patologia , PPAR gama/metabolismo , Análise de Sobrevida
3.
Cancer Sci ; 111(1): 112-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31675763

RESUMO

Drug repositioning is an emerging approach to developing novel cancer treatments. Vorinostat is a histone deacetylase inhibitor approved for cancer treatment, but it could attenuate its anticancer activity by activating the mTOR pathway. The HMG-CoA reductase inhibitor fluvastatin reportedly activates the mTOR inhibitor AMP-activated protein kinase (AMPK), and we thought that it would potentiate vorinostat's anticancer activity in renal cancer cells. The combination of vorinostat and fluvastatin induced robust apoptosis and inhibited renal cancer growth effectively both in vitro and in vivo. Vorinostat activated the mTOR pathway, as evidenced by the phosphorylation of ribosomal protein S6, and fluvastatin inhibited this phosphorylation by activating AMPK. Fluvastatin also enhanced vorinostat-induced histone acetylation. Furthermore, the combination induced endoplasmic reticulum (ER) stress that was accompanied by aggresome formation. We also found that there was a positive feedback cycle among AMPK activation, histone acetylation, and ER stress induction. This is the first study to report the beneficial combined effect of vorinostat and fluvastatin in cancer cells.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Fluvastatina/farmacologia , Neoplasias Renais/tratamento farmacológico , Vorinostat/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Renais/metabolismo , Fosforilação/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
4.
Oncology ; 98(1): 1-9, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31514196

RESUMO

Cytoreductive nephrectomy (CN) followed by systemic therapy had been considered the standard of care for metastatic renal cell carcinoma (mRCC) patients since two clinical trials established its role during the cytokines era. With introduction of new and effective drugs, such as vascular endothelial growth factor-targeted therapies, the role of CN started to be challenged. Retrospective studies conducted during the targeted therapy era pointed to better outcomes when CN was associated with systemic treatment, although certain patients with poor risk features did not seem to benefit. Therefore, prospective clinical trials supporting CN were needed. Recently, with the publication of two randomized trials evaluating CN in the targeted therapy era, it has been made clear that patient selection and multidisciplinary discussion are of paramount importance in order to achieve the best outcomes. We reviewed the available literature on the role of CN among mRCC patients, commenting on how to apply the new evidence into clinical practice and providing future perspectives.


Assuntos
Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Procedimentos Cirúrgicos de Citorredução , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Nefrectomia , Biomarcadores , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Citocinas/metabolismo , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Procedimentos Cirúrgicos de Citorredução/métodos , Prática Clínica Baseada em Evidências , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Metástase Neoplásica , Estadiamento de Neoplasias , Nefrectomia/efeitos adversos , Nefrectomia/métodos , Prognóstico , Resultado do Tratamento
5.
Cancer Sci ; 111(1): 59-71, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31729097

RESUMO

Low vitamin D status is associated with progression in patients with renal cell carcinoma (RCC). The present study found that vimentin, a mesenchymal marker, was accordingly upregulated, and E-cadherin, an epithelial marker, was downregulated in RCC patients with low vitamin D status. Thus, we investigated the effects of calcitriol or vitamin D3, an active form of vitamin D, on epithelial-mesenchymal transition (EMT) in RCC cells. RCC cells were treated by two models. In model 1, three RCC cell lines, ACHN, 786-O and CAKI-2, were incubated with either LPS (2.0 µg/mL) or transforming growth factor (TGF)-ß1 (10 ng/mL) in the presence or absence of calcitriol (200 nmol/L). In model 2, two RCC cell lines, ACHN and CAKI-2, were incubated with calcitriol (200 nmol/L) only. Calcitriol inhibited migration and invasion not only in TGF-ß1-stimulated but also in TGF-ß1-unstimulated RCC cells. Moreover, calcitriol suppressed E-cadherin downregulation and vimentin upregulation not only in TGF-ß1-stimulated but also in TGF-ß1-unstimulated ACHN and CAKI-2 cells. Calcitriol attenuated LPS-induced upregulation of MMP-2, MMP-7, MMP-9, MMP-26 and urokinase-type plasminogen activator (u-PA) in ACHN cells. In addition, calcitriol blocked TGF-ß1-induced nuclear translocation of ZEB1, Snail and Twist1 in ACHN and CAKI-2 cells. Mechanistically, calcitriol suppressed EMT through different signaling pathways: (i) calcitriol suppressed Smad2/3 phosphorylation by reinforcing physical interaction between vitamin D receptor (VDR) and Smad3 in TGF-ß1-stimulated RCC cells; (ii) calcitriol inhibited signal transducer and activator of transcription (STAT)3 activation in LPS-stimulated RCC cells; (iii) calcitriol inhibited ß-catenin/TCF-4 activation by promoting integration of VDR with ß-catenin in TGF-ß1-unstimulated RCC cells. Taken together, calcitriol inhibits migration and invasion of RCC cells partially by suppressing Smad2/3-, STAT3- and ß-catenin-mediated EMT.


Assuntos
Calcitriol/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Adulto , Idoso , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Renais/metabolismo , Masculino , Metaloendopeptidases/metabolismo , Pessoa de Meia-Idade , Fator de Transcrição STAT3/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , beta Catenina/metabolismo
6.
Int J Cancer ; 146(4): 1052-1063, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31259424

RESUMO

Sorafenib provides survival benefits in patients with advanced renal cell carcinoma (RCC), but its use is hampered by acquired drug resistance. It is important to fully clarify the molecular mechanisms of sorafenib resistance, which can help to avoid, delay or reverse drug resistance. Extracellular vesicles (EVs) can mediate intercellular communication by delivering effector molecules between cells. Here, we studied whether EVs are involved in sorafenib resistance of RCC and its possible molecular mechanisms. Using differential centrifugation, EVs were isolated from established sorafenib-resistant RCC cells (786-0 and ACHN), and EVs derived from sorafenib-resistant cells were uptaken by sensitive parental RCC cells and thus promoted drug resistance. Elevated exogenous miR-31-5p within EVs effectively downregulated MutL homolog 1 (MLH1) expression and thus promoted sorafenib resistance in vitro. Mice experiments also confirmed that miR-31-5p could mediate drug sensitivity in vivo. In addition, low expression of MLH1 was observed in sorafenib-resistant RCC cells and upregulation of MLH1 expression restored the sensitivity of resistant cell lines to sorafenib. Finally, miR-31-5p level in circulating EVs of RCC patients with progressive disease (PD) during sorafenib therapy was higher when compared to that in the pretherapy status. In conclusion, EVs shuttled miR-31-5p can transfer resistance information from sorafenib-resistant cells to sensitive cells by directly targeting MLH1, and thus magnify the drug resistance information to the whole tumor. Furthermore, miR-31-5p and MLH1 could be promising predictive biomarkers and therapeutic targets to prevent sorafenib resistance.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Vesículas Extracelulares/metabolismo , MicroRNAs/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Sorafenibe/farmacologia , Animais , Antineoplásicos/farmacologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Vesículas Extracelulares/genética , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína 1 Homóloga a MutL/biossíntese , Proteína 1 Homóloga a MutL/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mol Cell Biochem ; 465(1-2): 165-174, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31848806

RESUMO

Renal cell carcinoma (RCC) is a kind of malignant tumor with high recurrence, and it is urgent to find molecular markers for diagnosis and prognosis of RCC. Our study investigated the expression and function of integrin αMß2 in RCC cells, aiming to understand the role of integrin αMß2 in RCC and develop new therapeutic target for RCC. Overexpression and knockdown of lymphoid enhancer-binding factor 1 (LEF1) were performed using vector containing full-length cDNA and via siRNA technology, respectively. The expressions of mRNA and protein were detected by RT-PCR and Western blot, respectively. Proliferation of RCC cell was analyzed using WST-1 assay, and metastasis of RCC cell was evaluated using the transwell system. Our results demonstrated that LEF1 and integrin αMß2 were up-regulated in RCC cells via TGF-ß1-dependent mechanism, and LEF1 together with ß-catenin directly increased integrin αMß2 level. On the other hand, TGF-ß1-induced proliferation, migration and invasion were suppressed by function-blocking antibody against integrin αMß2 in RCC cells. In addition, integrin αMß2 is crucial for LEF1 mediated cell invasion by regulating MMP-2, MMP-9 and calpain-2 secretion in RCC cells. LEF1/integrin αMß2 expression was regulated by TGF-ß1, and LEF1/integrin αMß2 was involved in TGF-ß1's improvement effects on the proliferation and metastasis of RCC. Blocking integrin αMß2 activity could be a therapeutic option for patients with advanced RCC.


Assuntos
Carcinoma de Células Renais/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/biossíntese , Antígeno de Macrófago 1/metabolismo , Proteínas de Neoplasias/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Renais/patologia , Metástase Neoplásica
8.
Cancer Sci ; 111(3): 907-923, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31883418

RESUMO

The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment-naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression-free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD-L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval [CI]) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio [HR], 0.49; 95% CI, 0.152, 1.563) in patients with PD-L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD-L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD-L1+ tumors and irrespective of PD-L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD-L1 expression. Common treatment-emergent adverse events (all grade; grade ≥3) in each arm were hand-foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment-naive Japanese patients with advanced RCC, which is consistent with results in the overall population.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Sunitinibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Antígeno B7-H1/metabolismo , Carcinoma de Células Renais/metabolismo , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão
9.
Cancer Sci ; 111(3): 881-890, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31883420

RESUMO

TRIM44 has oncogenic roles in various cancers. However, TRIM44 expression and its function in renal cell carcinoma (RCC) are still unknown. Here in this study, we investigated the clinical significance of TRIM44 and its biological function in RCC. TRIM44 overexpression was significantly associated with clinical M stage, histologic type (clear cell) and presence of lymphatic invasion (P = .047, P = .005, and P = .028, respectively). Moreover, TRIM44 overexpression was significantly associated with poor prognosis in terms of cancer-specific survival (P = .019). Gain-of-function and loss-of-function studies using TRIM44 and siTRIM44 transfection showed that TRIM44 promotes cell proliferation and cell migration in two RCC cell lines, Caki1 and 769P. To further investigate the role of TRIM44 in RCC, we performed integrated microarray analysis in Caki1 and 769P cells and explored the data in the Oncomine database. Interestingly, FRK was identified as a promising candidate target gene of TRIM44, which was downregulated in RCC compared with normal renal tissues. We found that cell proliferation was inhibited by TRIM44 knockdown and then recovered by siFRK treatment. Taken together, the present study revealed the association between high expression of TRIM44 and poor prognosis in RCC patients and that TRIM44 promotes cell proliferation by regulating FRK.


Assuntos
Carcinoma de Células Renais/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Renais/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais/fisiologia
10.
Anticancer Res ; 39(12): 6939-6943, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810965

RESUMO

BACKGROUND/AIM: In spite of early detection, appoximately 15% of the small renal cell carcinomas (RCC) will develop metastasis within 5 years follow-up. The aim of this study was to identify new biomarkers to estimate the postoperative relapse of the most common conventional RCC. PATIENTS AND METHODS: Tissue multi arrays of conventional RCC without metastasis at the time of operation from a cohort of 634 patients were analysed by immunohistochemistry for expression of the chitinase 3-like protein 2 (CHI3L2). Cancer specific survival of patients was estimated with Kaplan-Meier analysis, univariate and multivariate Cox regression models. RESULTS: Kaplan-Meier analysis estimated a shorter cancer-free survival for patients with CHI3L2 positive tumors. In multivariate analysis, the CHI3L2 positivity associated with a 3.5 times higher risk for tumor relapse (p<0.001). CONCLUSION: Expression of CHI3L2 in tumor cells of conventional RCC define a group of patients at high risk for postoperative progression.


Assuntos
Carcinoma de Células Renais/metabolismo , Quitinases/metabolismo , Neoplasias Renais/metabolismo , Macrófagos/metabolismo , Recidiva Local de Neoplasia/metabolismo , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/cirurgia , Quitinases/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Nefrectomia , Prognóstico , Análise de Sobrevida , Análise Serial de Tecidos , Regulação para Cima
11.
Bull Cancer ; 106(12): 1177-1189, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31610911

RESUMO

Inactivating germline pathogenic variants of the DICER1 gene are responsible for a spectrum of rare diseases, which expanded a lot in recent years. The constitution of an U.S. registry with these patients and their families as well as the registration of patients in European databases of rare tumors helped to better identify diseases encountered in this syndrome but also to study its pathophysiology (major role in miRNA maturation and recently discovered functions, e.g. in genome integrity maintenance). Most encountered disorders are pediatric malignancies, mainly the pulmonary pneumoblastoma and Sertoli-Leydig tumours. However, benign pathologies such as thyroid goiters, cystic nephromas or pulmonary cystic lesions are also frequently reported. Homogeneous guidelines regimens written by the European groups working on very rare pediatric tumors are proposed but it is important to underscore that they rely on rare scientific data; therefore overall consensus remains precarious. The genetic counseling to families is still difficult due to the large observed spectrum of tumors and the incomplete penetrance. In this article, the authors update current knowledge on the DICER1 syndrome.


Assuntos
RNA Helicases DEAD-box/genética , Neoplasias/genética , Doenças Raras/genética , Ribonuclease III/genética , RNA Helicases DEAD-box/metabolismo , Feminino , Aconselhamento Genético , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Doenças Raras/diagnóstico , Doenças Raras/metabolismo , Ribonuclease III/metabolismo , Síndrome
12.
Anticancer Res ; 39(10): 5369-5374, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570431

RESUMO

BACKGROUND/AIM: Cytokine-induced killer (CIK) cells are ex vivo expanded major histocompatibility complex (MHC)-unrestricted cytotoxic cells with promising effects against a variety of cancer types. Regulatory T-cells (T-reg) have been shown to reduce the effectiveness of CIK cells against tumor cells. Peptide P60 has been shown to inhibit the immunosuppressive functions of T-regs. This study aimed at examining the effect of p60 on CIK cells efficacy against renal and pancreatic cancer cells. MATERIALS AND METHODS: The effect of P60 on CIK cytotoxicity was examined using flow cytometry, WST-8-based cell viability assay and interferon γ (IFNγ) ELISA. RESULTS: P60 treatment resulted in a significant decrease in the viability of renal and pancreatic cancer cell lines co-cultured with CIK cells. No increase in IFNγ secretion from CIK cells was detected following treatment with P60. P60 caused no changes in the distribution of major effector cell populations in CIK cell cultures. CONCLUSION: P60 may potentiate CIK cell cytotoxicity against tumor cells.


Assuntos
Células Matadoras Induzidas por Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Fatores de Transcrição Forkhead/antagonistas & inibidores , Neoplasias Renais/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura/métodos , Células Matadoras Induzidas por Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Neoplasias Renais/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
13.
Anticancer Res ; 39(10): 5427-5436, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570437

RESUMO

BACKGROUND/AIM: Renal cell carcinoma (RCC) is one of the most common tumor diseases in adults, and new specific biomarkers are urgently needed to define diagnosis and prognosis of patients with RCC as well as monitor the outcome of therapeutic interventions. The enzyme nicotinamide N-methyltransferase (NNMT) is believed to represent such a marker molecule in RCC therapy. MATERIALS AND METHODS: NNMT expression was examined by western blotting in samples from patients with RCC and in RCC cell lines. Effects of NNMT on cell growth and metabolism were assessed using the Hoechst 33342 reagent assay and Vita-Orange cell viability assay. Incubation experiments were performed to study the influence of methionine and interleukin-6 (IL6) on expression of NNMT. RESULTS: In patient samples, NNMT was up-regulated depending on the stage of progression. Investigations in an RCC cell culture model showed that after modulation of NNMT expression, cellular metabolism, but not cell growth was affected. This regulatory function was also dependent on the presence of the NNMT precursor substrate methionine and IL6. CONCLUSION: The metabolism-regulatory activity of NNMT depends on the precursor substrate methionine and the presence of IL6. The function of methionine appears to be dependent on the stage of progression, since in individual RCC cell lines, opposing effects on metabolism were demonstrated. This, in turn, reflects the thoroughly complex situation in the clinic.


Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Metionina/metabolismo , Nicotinamida N-Metiltransferase/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Progressão da Doença , Células HEK293 , Humanos , Interleucina-6/metabolismo , Prognóstico , Regulação para Cima/fisiologia
14.
Curr Urol Rep ; 20(11): 68, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31605269

RESUMO

PURPOSE OF REVIEW: To critically review the potential clinical applications of prostate-specific membrane antigen (PSMA) radioactive ligands in renal cell carcinoma (RCC). RECENT FINDINGS: Radioactive probes targeting PSMA hold promise in several malignancies in addition to prostate cancer, owing to the expression of PSMA by tumor neovasculature. The majority of clear cell RCCs (ccRCC), the most malignant RCC subtype, express PSMA on tumor-associated neovasculature. The endothelium of less aggressive RCC subtypes is PSMA positive in a lower, but still significant percentage of cases. PSMA might therefore represent an interesting theragnostic target in RCC. The preliminary data available suggest a potential role for PSMA-targeting radiopharmaceuticals in complementing conventional imaging for staging ccRCC patients at risk of nodal involvement and oligometastatic disease. Additional applications of PSMA imaging may be the selection and the response assessment of patients receiving anti-angiogenic treatments. The effectiveness of PSMA-targeting radionuclide therapy should also be investigated.


Assuntos
Antígenos de Superfície , Carcinoma de Células Renais/diagnóstico por imagem , Glutamato Carboxipeptidase II , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Antígenos de Superfície/metabolismo , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Humanos , Neoplasias Renais/metabolismo , Estadiamento de Neoplasias , Compostos Radiofarmacêuticos , Resultado do Tratamento
15.
Neoplasma ; 66(6): 946-953, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607131

RESUMO

The aim of this study was to determine the expression levels of TTK in clear cell renal cell carcinoma (ccRCC) tissues and its possible link with the clinical pathologic characteristics and the prognosis of patients suffering this disease, and to further explore the potential role of TTK in the progression of ccRCC. Immunohistochemical (IHC) assays were performed to detect the expression levels of TTK in 112 samples of ccRCC tissues and corresponding non-tumor tissues. According to the results of IHC assays, patients were divided into TTK high expression and low expression group. Clinical analysis related to the clinical features (age, gender, T stage), and the potential link between TTK expression levels and clinical features were analyzed. In addition, the effects of TTK on the proliferation and invasion of ccRCC cells were detected through colony formation assay and transwell assays, respectively. The possible effects of TTK on tumor growth and metastasis were measured in mice. We found a high expression level of TTK in human ccRCC tissues from patients who received surgical treatment. We also found its expression level was obviously associated with clinical characteristics, such as T stage (p=0.008) and lymphatic metastasis (p=0.023). We further confirmed that knockdown of TTK suppressed cell proliferation and invasion in 2 types of ccRCC cells, HTB-47 and CRL-1932 cells. Furthermore, TTK contributes to tumor growth and metastasis of ccRCC in mice. We found that TTK affected the progression of ccRCC and further mechanically confirmed it could be a novel therapeutic target for ccRCC treatment.


Assuntos
Carcinoma de Células Renais/patologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias Renais/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/metabolismo , Camundongos , Metástase Neoplásica , Prognóstico
16.
Curr Radiopharm ; 12(3): 211-219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31612808

RESUMO

BACKGROUND: Nephrotoxicity is a prevalent consequence of cancer treatment using radiotherapy and chemotherapy or their combination. There are two methods; histological and biochemical, to assess the kidney damage caused by toxic agents in animal studies. Although these methods are used for the try-out of renoprotective factors, these methods are invasive and time-consuming, and also, lack the necessary sensitivity for primary diagnosis. Quantitative renal 99mTc-DMSA scintigraphy is a noninvasive, precise and sensitive radionuclide technique which is used to assess the extent of kidney damage, so that the extent of injury to the kidney will be indicated by the renal uptake rate of 99mTc-DMSA in the kidney. In addition, this scintigraphy evaluates the effect of the toxic agents by quantifying the alterations in the biodistribution of the radiopharmaceutical. CONCLUSION: In this review, the recent findings about the renoprotective agents were evaluated and screened with respect to the use of 99mTc-DMSA , which is preclinically and clinically used for animal cases and cancer patients under the treatment by radiotherapy and chemotherapy.


Assuntos
Neoplasias Renais/metabolismo , Rim/metabolismo , Substâncias Protetoras/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Ácido Dimercaptossuccínico Tecnécio Tc 99m/farmacocinética , Animais , Humanos , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Rim/efeitos da radiação , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/radioterapia , Cintilografia
17.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(12): 158525, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513923

RESUMO

Clear cell renal cell carcinoma (ccRCC), which accounts for the majority of kidney cancer, is known to accumulate excess cholesterol. However, the mechanism and functional significance of the lipid accumulation for development of the cancer remains obscure. In this study, we analyzed 42 primary ccRCC samples, and determined that cholesterol levels of ~ 70% of the tumors were at least two-fold higher than that of benign kidney tissues. Compared to tumors without cholesterol accumulation, those containing excess cholesterol expressed higher levels of scavenger receptor BI (SR-B1), a receptor for uptake of HDL-associated cholesterol, but not genes involved in cholesterol synthesis and uptake of LDL-associated cholesterol. To further determine the roles of sterol accumulation for cancer development, we implanted ccRCC from patients into mouse kidneys using a mouse ccRCC xenograft model. Feeding mice with probucol, a compound lowing HDL-cholesterol, markedly reduced levels of cholesterol in tumors containing excess cholesterol. This treatment, however, did not affect growth of these tumors. Our study suggests that cholesterol overaccumulation in ccRCC is the consequence of increased uptake of HDL-cholesterol as a result of SR-B1 overexpression, but the lipid accumulation by itself may not play a significant role in progression of the cancer.


Assuntos
Carcinoma de Células Renais/metabolismo , HDL-Colesterol/metabolismo , Neoplasias Renais/metabolismo , Animais , Transporte Biológico , Carcinoma de Células Renais/patologia , Humanos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/patologia , Metabolismo dos Lipídeos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID
18.
Nat Commun ; 10(1): 4346, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554815

RESUMO

Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase   (IDO/TDO) inhibitors.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Melanoma/tratamento farmacológico , Metabolômica , Nivolumabe/uso terapêutico , Adaptação Fisiológica/efeitos dos fármacos , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/metabolismo , Ensaios Clínicos como Assunto , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/sangue , Neoplasias Renais/metabolismo , Cinurenina/sangue , Masculino , Melanoma/sangue , Melanoma/metabolismo , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Resultado do Tratamento , Triptofano/sangue
19.
Oncol Rep ; 42(5): 1972-1980, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545449

RESUMO

Perirenal adipose tissue (PAT) has been implicated in renal cell carcinoma (RCC). The expression of uncoupling protein 1 (UCP1) is higher in PAT compared with that in back subcutaneous adipose tissue (bSAT). The aim of the present study was to determine UCP1 expression in different parts of PAT and to analyze the correlation between UCP1 expression in PAT and RCC. PAT from the upper and lower renal poles and bSAT samples were collected from 50 patients with RCC (RCC group) and 54 patients with renal cysts (control group) who had undergone renal surgery. Both UCP1 mRNA and protein levels were found to be significantly higher and adipocytes appeared to be smaller in the PAT of the RCC group. Furthermore, the RCC group had more multilocular UCP1­positive adipocytes. UCP1 staining in the PAT was significantly stronger in the RCC group, but there was no significant difference in UCP1 staining in the bSAT between the two groups. Furthermore, Fuhrman grade and T stage were higher in the high UCP1 expression group of RCC patients. In conclusion, high UCP1 expression in the PAT may serve as an indicator of poor prognosis in RCC.


Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Gordura Subcutânea/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Regulação para Cima , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Gordura Subcutânea/patologia
20.
Int J Mol Sci ; 20(19)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547100

RESUMO

Naturally existing Chlorogenic acid (CGA) is an antioxidant-rich compound reported to act a chemopreventive agent by scavenging free radicals and suppressing cancer-causing mechanisms. Conversely, the compound's poor thermal and pH (neutral and basic) stability, poor solubility, and low cellular permeability have been a huge hindrance for it to exhibit its efficacy as a nutraceutical compound. Supposedly, encapsulation of CGA in chitosan nanoparticles (CNP), nano-sized colloidal delivery vector, could possibly assist in enhancing its antioxidant properties, in vitro cellular accumulation, and increase chemopreventive efficacy at a lower concentration. Hence, in this study, a stable, monodispersed, non-toxic CNP synthesized via ionic gelation method at an optimum parameter (600 µL of 0.5 mg/mL of chitosan and 200 µL of 0.7 mg/mL of tripolyphosphate), denoted as CNP°, was used to encapsulate CGA. Sequence of physicochemical analyses and morphological studies were performed to discern the successful formation of the CNP°-CGA hybrid. Antioxidant property (studied via DPPH (1,1-diphenyl-2-picrylhydrazyl) assay), in vitro antiproliferative activity of CNP°-CGA, and in vitro accumulation of fluorescently labeled (FITC) CNP°-CGA in cancer cells were evaluated. Findings revealed that successful formation of CNP°-CGA hybrid was reveled through an increase in particle size 134.44 ± 18.29 nm (polydispersity index (PDI) 0.29 ± 0.03) as compared to empty CNP°, 80.89 ± 5.16 nm (PDI 0.26 ± 0.01) with a maximal of 12.04 µM CGA loaded per unit weight of CNP° using 20 µM of CGA. This result correlated with Fourier-Transform Infrared (FTIR) spectroscopic analysis, transmission Electron Microscopy (TEM) and field emission scanning (FESEM) electron microscopy, and ImageJ evaluation. The scavenging activity of CNP°-CGA (IC50 5.2 ± 0.10 µM) were conserved and slightly higher than CNP° (IC50 6.4±0.78 µM). An enhanced cellular accumulation of fluorescently labeled CNP°-CGA in the human renal cancer cells (786-O) as early as 30 min and increased time-dependently were observed through fluorescent microscopic visualization and flow cytometric assessment. A significant concentration-dependent antiproliferation activity of encapsulated CGA was achieved at IC50 of 16.20 µM as compared to CGA itself (unable to determine from the cell proliferative assay), implying that the competent delivery vector, chitosan nanoparticle, is able to enhance the intracellular accumulation, antiproliferative activity, and antioxidant properties of CGA at lower concentration as compared to CGA alone.


Assuntos
Carcinoma de Células Renais , Quitosana , Ácido Clorogênico , Sistemas de Liberação de Medicamentos , Depuradores de Radicais Livres , Neoplasias Renais , Nanopartículas , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Quitosana/química , Quitosana/farmacocinética , Quitosana/farmacologia , Ácido Clorogênico/química , Ácido Clorogênico/farmacocinética , Ácido Clorogênico/farmacologia , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/farmacocinética , Fluoresceína-5-Isotiocianato/farmacologia , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacocinética , Depuradores de Radicais Livres/farmacologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Microscopia de Fluorescência , Nanopartículas/química , Nanopartículas/uso terapêutico
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