Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.011
Filtrar
1.
Life Sci ; 234: 116768, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445027

RESUMO

In prostate cancer development, the androgen receptor (AR) signaling plays a crucial role during both formation of early prostate lesions and progression to the lethal, incurable castration resistant stage. Accordingly, numerous approaches have been developed to inhibit AR activity including androgen deprivation therapy, application of the AR antagonists as well as the use of taxanes. However, these treatments, although effective initially, resistance inevitably occur for most of the patients within several years and limiting the therapeutic efficacy. Of note, alterations and reactivation of the AR signaling pathway have been demonstrated as the major reasons for the observed resistance. Accumulating evidences have suggested that synthesis of AR splicing variants, in particular, the constitutively active AR-V7, is one of the most important mechanisms that contribute to the abnormal AR signaling. In addition, clinical data also highlight the potential of using AR-V7 as a predictive biomarker and a therapeutic target in metastatic castration resistant prostate cancer (mCRPC). In this review, we summarize the recent findings concerning the specific role of AR-V7 in CRPC progression, drug resistance and its potential value in clinical assessment.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Taxoides/uso terapêutico , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Antineoplásicos/farmacologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taxoides/farmacologia
2.
Anticancer Res ; 39(8): 4285-4289, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366519

RESUMO

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is a cancer with poor prognosis due to therapy resistance, locoregional recurrences, and distant metastases. There is on increased interest in profiling the androgen receptor (AR) in cancer biology. The aim of this study was to compare AR and Ki-67 levels in the neoplastic epithelium and stroma between non-metastatic and metastatic stages of OSCC. PATIENTS AND METHODS: Tissue specimens of 101 non-metastatic and 95 metastatic OSCC patients were analyzed by immunohistochemistry. RESULTS: More than 20% of AR-positive cytoplasmic staining of OSCC epithelium was significantly associated with nuclear AR levels in the epithelium and increased AR levels in the stroma. In metastatic OSCC patients, Ki-67 was significantly higher than in non-metastatic OSCC patients. CONCLUSION: More than 20% of AR-positive cytoplasmic staining in neoplastic OSSC epithelium is a significant predictor of OSCC progression risk.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Antígeno Ki-67/genética , Neoplasias Bucais/genética , Receptores Androgênicos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Fatores de Risco
3.
Cell Physiol Biochem ; 53(1): 215-228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31299143

RESUMO

BACKGROUND/AIMS: With the prevalence of asthma being greater in women, detrimental effects of female sex steroids have been explored, but potential protective effects of androgens are not established. Airway smooth muscle (ASM) is a key cell type in contractility and remodelling of asthma. There are no data on expression and functionality of androgen receptor (AR) in human ASM cells. METHODS: We used primary human ASM cells from non-asthmatics vs. asthmatics to determine AR expression at baseline and with inflammation measured using Western blotting/qRT-PCR, and the role of AR in regulating intracellular Ca2+ ([Ca2+]i) measured using Fluo-3 loaded real time [Ca2+]i imaging. RESULTS: We found that compared to females, baseline AR is greater in male ASM and increases with inflammation/asthma. Androgens, via AR, blunted TNFα or IL-13-induced enhancement of ASM [Ca2+]i in both males and females, with retained efficacy in asthmatics. AR effects involve reduced Ca2+ influx via L-type channels and store-operated Ca2+ entry, the latter by downregulating STIM1 and Orai1 and increasing TMEM66. CONCLUSION: Our data show AR expression is increased in female ASM with asthma, but has retained functionality that could be used to reduce [Ca2+]i towards alleviating airway hyperresponsiveness.


Assuntos
Cálcio/metabolismo , Receptores Androgênicos/metabolismo , Asma/metabolismo , Asma/patologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Interleucina-13/farmacologia , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/química , Receptores Androgênicos/genética , Fatores Sexuais , Molécula 1 de Interação Estromal/metabolismo , Testosterona/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
4.
Molecules ; 24(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052610

RESUMO

BACKGROUND: The aim of this study was to simplify and identify the contents of the herbal formula, HBX-5. This study was carried out to evaluate the therapeutic effects of HBX-6 in a mouse model of benign prostatic hyperplasia (BPH). Based on in vitro, we selected a candidate, reconstituted an experimental agent and investigated the effects on testosterone-induced BPH rats. Cell viability was determined by MTT assay in RWPE-1 and WPMY-1 cells. The expression of androgen receptor (AR) was measured in dihydrotestosterone-stimulated RWPE-1 and WPMY-1 cells. BPH was induced in mice by a subcutaneous injection of testosterone propionate for four weeks. Animals were divided into six groups: Group 1, control mice; Group 2, mice with BPH; Group 3, mice with BPH treated with finasteride; Group 4, mice with BPH treated with 200 mg/kg HBX-5; Group 5, mice with BPH treated with 100 mg/kg HBX-6; and Group 6, mice with BPH treated with 200 mg/kg HBX-6. Changes in prostate weight were measured after treatments, and the thickness of the epithelium was evaluated. The expression levels of proteins associated with prostatic cell proliferation and cell cycle-related proteins were determined. Based on previous reports and in vitro results, we selected Cornus officinalis and Psoralea corylifolia among HBX-5 components and reconstituted the experimental agent, and named it HBX-6. The result represented a new herbal formula, HBX-6 that suppressed the pathological alterations in BPH and showed a marked reduction in proliferation-related protein expression compared to mice with BPH. Our results indicate that HBX-6 has a better therapeutic effect in the BPH murine model than those of HBX-5 and finasteride, suggesting the role of HBX-6 as a new BPH remedial agent.


Assuntos
Cornus/química , Fator de Transcrição E2F1/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/metabolismo , Psoralea/química , Animais , Ciclo Celular , Linhagem Celular , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo
5.
Medicine (Baltimore) ; 98(19): e15608, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083254

RESUMO

BACKGROUND: androgen receptor variant 7 (AR-V7) has been suggested as potential marker for treatment selection in men with metastatic castration-resistant prostate cancer (mCRPC). The aim of the present review is to critically analyze: frequency of the AR-V7 expression in mCRPC cases-impact of AR-V7 expression on abiraterone, enzalutamide, and taxane therapy. METHODS: we searched in the Medline and Cochrane Library database from the literature of the past 10 years. We critically evaluated the level of evidence according to the European Association of Urology (EAU) guidelines. RESULTS: 12 clinical trials were selected. The determination of AR-V7 in peripheral blood using circulating tumor cells mRNA seems to be the preferred method. At baseline, the mean percentage of cases with AR-V7 positivity was 18.3% (range 17.8%-28.8%). All data on mCRPC submitted to enzalutamide or abiraterone reported a significantly (P <.05) lower clinical progression-free survival (CPFS) and overall survival (OS) in AR-V7+ than AR-V7- cases (CPFS hazard ratio [HR]: 2.3; 95% CI 1.1-4.9; OS HR: 3.0; 95% CI 1.4-6.3). In mCRPC cases submitted to chemotherapies data are not homogeneous and some studies showed no association between CPFS or OS and AR-V7 status (OS HR 1.6; 95% CI 0.6-4.4; P = .40). CONCLUSIONS: the suggestion is that taxane therapy is more efficacious than abiraterone or enzalutamide for men with AR-V7+ CRPC. On the contrary, clinical outcomes did not seem to differ significantly on the basis of the type of therapy used among AR-V7- cases.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Androstenos/uso terapêutico , Biomarcadores Tumorais/genética , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Variação Genética , Humanos , Masculino , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Taxoides/uso terapêutico
6.
Nat Commun ; 10(1): 2034, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048691

RESUMO

Polyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds in certain human proteins is the cause of polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, we addressed how the conformation of the polyQ tract of the androgen receptor, associated with spinobulbar muscular atrophy (SBMA), depends on its length. Here we report that this sequence folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups, and that its helicity directly correlates with tract length. These unusual hydrogen bonds are bifurcate with the conventional hydrogen bonds stabilizing α-helices. Our findings suggest a plausible rationale for the association between polyQ tract length and androgen receptor transcriptional activity and have implications for establishing the mechanistic basis of SBMA.


Assuntos
Atrofia Bulboespinal Ligada ao X/genética , Peptídeos/química , Conformação Proteica em alfa-Hélice/genética , Receptores Androgênicos/química , Fatores de Transcrição/química , Atrofia Bulboespinal Ligada ao X/patologia , Dicroísmo Circular , Glutamina/química , Humanos , Hidrogênio/química , Ligações de Hidrogênio , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Mutação , Agregados Proteicos/genética , Receptores Androgênicos/genética , Fatores de Transcrição/genética
7.
Hum Cell ; 32(3): 379-389, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31119584

RESUMO

Men are at a higher risk of developing bladder cancer than women. Although the urinary bladder is not regarded as an sex organ, it has the potential to respond to androgen signals. The mechanisms responsible for the gender differences remain unexplained. Androgen receptor (AR) after binding with 5α-dihydrotestosteron (DHT) undergoes a conformational change and translocates to nucleus to induce transcriptional regulation of target genes. However androgen/AR signaling can also be activated by interacting with several signaling molecules and exert its non-genomic function. The aim of present study was to explain whether the progression of bladder cancer in men is dependent on androgen/AR signaling. Studies were carried out on human bladder cancer cell lines: HCV29, T24, HT1376 and HTB9. Bladder cancer cells were treated for 48 h with 10 nM DHT or not, with replacement after 24 h. Expression of cell signaling proteins, was analyzed using Western Blot and RT-PCR. Subcellular localization of protein was studied using the ProteoExtract Subcellular Proteome Extraction Kit and Western blot analysis. We showed that DHT treatment significantly increased AR expression in bladder cell line HCV29. We also observed DHT-mediated activation of Akt/GSK-3ß signaling pathway which plays a central role in cancer progression. Presented results also show that androgen/AR signaling is implicated in phosphorylation of eIF4E which can promote epithelial-mesenchymal transition (EMT). We indicate that AR plays an essential role in bladder cancer progression in male patients. Therefore, androgen-activated AR signaling is an attractive regulatory target for the inhibition or prevention of bladder cancer incidence in men.


Assuntos
Di-Hidrotestosterona/metabolismo , Di-Hidrotestosterona/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/genética , Células Cultivadas , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Terapia de Alvo Molecular , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Risco , Caracteres Sexuais , Transdução de Sinais/genética , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/terapia
8.
Indian J Pathol Microbiol ; 62(2): 226-231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30971545

RESUMO

Background: Male breast cancers (MBCs) are uncommon and account for 1% of all breast cancers. Medical conditions that increase the estrogen to testosterone ratio are implicated as the risk factors. Morphologically similar, but MBCs have biological differences compared with female breast cancer (FBC). Purpose: The present study was aimed to examine the immunophenotype of MBC, subsequent molecular subtypes, their association with clinicopathological features, and prognosis. Materials and Methods: We analyzed clinicopathological features of 42 cases of MBC, and classified them according to molecular classification using immunohistochemistry (IHC). This is the second largest study from India. Results and Conclusion: Median age of patients was 61 years (age range: 41-87 years). Invasive duct carcinoma comprised 95.2% of cases. Tumor grade II and III was seen in 50% and 47.6% of cases, respectively, and advanced stage disease (III/IV) was seen in 45.2% cases (n = 39). Estrogen receptor (ER) was positive in 97.6% cases, progesterone receptor (PR) in 83.3%, androgen receptor (AR) in 76.2%, HER2 in 4.8%, Cyclin-D1 in 92.9%, Bcl2 in 66.7%, GCDFP-15 in 23.8%, p53 in 16.7%, and Ki67 index was low (<14%) in 66.7% cases. Molecular subtyping of these cases revealed 64.3% of luminal A, 35.7% of luminal B, and no HER2 rich/driven category or triple negative case. There was no statistical significance between luminal A and B category pertaining to overall stage of tumor (P = 0.905). Lymph node metastasis was more commonly associated with luminal B category (P = 0.089). p53 positivity showed significant association with luminal A cases (P = 0.002) and nodal metastasis (P = 0.042). GCDFP-15 positivity showed significant association with higher tumor grade (P = 0.042) and stage (P = 0.047). Stage was the most significant prognostic marker (P < 0.0001). On follow-up (n = 27), all the six cases that showed recurrence/persistent disease were high stage (III/IV) on presentation.


Assuntos
Neoplasias da Mama Masculina/classificação , Neoplasias da Mama Masculina/diagnóstico , Imunofenotipagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Ductal de Mama/diagnóstico , Humanos , Imuno-Histoquímica , Índia , Antígeno Ki-67/genética , Metástase Linfática/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/genética , Receptores Androgênicos/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Centros de Atenção Terciária
9.
BMC Cancer ; 19(1): 331, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961575

RESUMO

BACKGROUND: Non-muscular invasive bladder cancer (NMIBC) has a high risk of recurrence. As androgen receptor (AR) reportedly affects bladder cancer, we assessed the correlation between NMIBC recurrence and tumor AR expression in Japanese patients. METHODS: We retrospectively reviewed 53 specimens of non-metastatic NMIBC, with recurrence-free survival (RFS) as the primary endpoint. We used real-time quantitative polymerase chain reaction to quantify AR mRNA expression. Kaplan-Meier product-limit estimators were used to assess RFS distribution, log-rank tests to analyze differences in RFS between high- and low-risk groups; and multivariate analyses of AR mRNA expression and other clinicopathological factors to predict independent factors for RFS. RESULTS: The high AR mRNA-expressing group (n = 43) tended to have a longer median RFS (not reached) than did the low-AR group (n = 10; 9.04 months; P = 0.112). Multivariate analysis showed female sex (hazard ratio [HR]: 7.360, 95% CI: 1.649-32.856, P = 0.009), tumor size ≥3 cm (HR: 23.697, 95% CI: 4.383-128.117, P < 0.001) and low AR mRNA expression (HR: 0.202, 95% CI: 0.048-0.841, P = 0.028) to be independent predictors of shorter RFS. CONCLUSION: Our study showed that low AR mRNA expression level is an independent risk factor for RFS in Japanese patients with NMIBC. Further studies are necessary but AR expression might be a new indicator of recurrence of NMIBC.


Assuntos
Biomarcadores Tumorais/metabolismo , RNA Mensageiro/metabolismo , Receptores Androgênicos/metabolismo , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Cistectomia/métodos , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Valor Preditivo dos Testes , Prognóstico , RNA Mensageiro/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Receptores Androgênicos/genética , Estudos Retrospectivos , Fatores de Risco , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/cirurgia
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(4): 360-362, 2019 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-30950026

RESUMO

OBJECTIVE: To detect potential variant of AR gene in an infant with complete androgen insensitivity syndrome. METHODS: The coding regions and splicing sites of the AR gene were subjected to PCR amplification and direct DNA sequencing. Fluorescence quantitative PCR was also used to detect copy number alterations of exons 2 to 8 of the AR gene. RESULTS: Deletion of exons 2 to 8 was detected in the proband, and the results were verified among the family members. CONCLUSION: Hemizygotic deletion of exons 2 to 8 of the AR gene probably underlies the complete androgen insensitivity syndrome in this infant.


Assuntos
Síndrome de Resistência a Andrógenos , Receptores Androgênicos/genética , Síndrome de Resistência a Andrógenos/genética , Sequência de Bases , Éxons , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase
11.
Molecules ; 24(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010227

RESUMO

Endocrine active compounds with structural similarities to natural hormones such as 17ß-estradiol (E2) and androgen are suspected to affect the human endocrine system by inducing hormone-dependent effects. This study aimed to detect the (anti-)estrogenic and (anti-)androgenic activities of mono-(2-ethylhexyl) phthalate (MEHP) by yeast estrogen/androgen bioassay (YES/YAS). In addition, the mechanism and uptake of MEHP to receptors during agonistic and antagonistic activities were investigated through the activation signal recovery test and chromatographic analysis using liquid chromatography and tandem mass spectrometry (LC-MS/MS). Estrogenic and androgenic activities of MEHP were not observed. However, MEHP exhibited anti-estrogenic (IC50 = 125 µM) and anti-androgenic effects (IC50 = 736 µM). It was confirmed that these inhibitory effects of MEHP were caused by receptor-mediated activity of the estrogen receptor and non-receptor-mediated activity of the androgen receptor in an activation signal recovery test. When IC50 concentrations of anti-estrogenic and androgenic activity of MEHP were exposed to yeast cells, the uptake concentration observed was 0.0562 ± 0.0252 µM and 0.143 ± 0.0486 µM by LC-MS/MS analysis.


Assuntos
Bioensaio/métodos , Dietilexilftalato/análogos & derivados , Disruptores Endócrinos/farmacologia , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Intervalos de Confiança , Dietilexilftalato/farmacologia , Feminino , Humanos , Receptores Androgênicos/genética , Receptores Estrogênicos/genética , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Espectrometria de Massas em Tandem
12.
Andrologia ; 51(5): e13250, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30815925

RESUMO

In this study, we aimed to determine androgen receptor (AR) and SRD5A2 gene mutations in 45 patients characterised by 46,XY Disorders of Sex Differentiation (DSD) signs with normal testicular development referred to the Children's Medical Center from February 2015 to September 2017. Karyotype and sex hormone analyses were performed. Cytogenetic investigation showed that seven patients were 46,XX DSD, six patients were chromosomal DSD and 32 patients were 46,XY DSD. Eight exons of the AR gene and five exons of the SRD5A2 gene were amplified. Two cases were affected with androgen insensitivity syndrome (AIS) (missense mutation on exon 7, position c.3637 G>A: p.R841H and position c.3610 G>A: p.R832Q), one case was affected with 5-alpha-reductase deficiency type 2 (missense mutation at c.578A>G: p.N193S on exon 4), and 22 cases (88%) did not demonstrate AIS or 5α-RD2 gene abnormality. Due to the great impact of these disorders on human lifestyle, evaluation of genes involved can improve genetic counselling and therapeutic management. We focused on the AR and SRD5A2 genes in patients with 46,XY DSDs with normal testicular development referred to the Children's Medical Center from all over the country to eventually culminate in a reliable prenatal diagnosis protocol at this major referral centre giving service to a great number of families with consanguineous marriages.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética , Proteínas de Membrana/genética , Receptores Androgênicos/genética , Testículo/crescimento & desenvolvimento , Adolescente , Adulto , Criança , Pré-Escolar , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Éxons/genética , Aconselhamento Genético , Humanos , Irã (Geográfico) , Cariotipagem , Masculino , Mutação de Sentido Incorreto
13.
Ecotoxicol Environ Saf ; 175: 208-214, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30901638

RESUMO

The widely used surfactant nonylphenol ethoxylate (NPEO) and its raw material 4-n-nonylphenol (4-n-NP), as well as its degradation products, are recognized as endocrine disrupting chemicals. The USA Environmental Protection Agency (EPA) released an assessment that looked for safe alternatives to NPEO. Vanillin ethoxylate (VAEO) is a novel substitute for NPEO and is quite similar to NPEO in structure; there is a risk that it has similar endocrine disrupting effects to NPEO. However, their effects on various nuclear hormone receptors have not been thoroughly examined. In this study, the effects of NPEO, VAEO, 4-n-NP and Vanillin on the estrogen receptor α (ERα), androgen receptor (AR), thyroid hormone receptor (TR), retinoic X receptor ß (RXRß) and estrogen-related receptor γ (ERRγ) were determined and compared using a battery of recombined yeast strains expressing ß-galactosidase. The results showed that NPEO and 4-n-NP acted as significant antagonists of ER, AR, TR and ERRγ. In addition, 4-n-NP also had antagonistic activity toward RXRß. Moreover, VAEO was shown to be a very weak antagonist of TR and ERRγ, and Vanillin had no interaction with any nuclear receptors. For the first time, it was found that NPEO had AR, TR and ERRγ antagonistic effects and that 4-n-NP was an antagonist of RXRß. The in vitro data indicated that NPEO, 4-n-NP and VAEO have the potential to act as endocrine disruptors involving more than one nuclear hormone receptor, but VAEO has much lower endocrine disrupting potential than NPEO. Thus, it is critical to find safe substitutes for NPEO and a substitute of NPEO with structural analogues should be carried out with caution. Furthermore, to look for preferable alternatives for NPEO, more in vivo and in vitro studies of the alternatives concerning endocrine disruption are needed, especially in vitro studies need to involve various target points, not only focus on their effects on ER but also take other nuclear hormone receptor pathways into consideration.


Assuntos
Benzaldeídos/toxicidade , Disruptores Endócrinos/toxicidade , Etilenoglicóis/toxicidade , Fenóis/toxicidade , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Benzaldeídos/química , Relação Dose-Resposta a Droga , Disruptores Endócrinos/química , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , Etilenoglicóis/química , Estrutura Molecular , Fenóis/química , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores dos Hormônios Tireóideos/antagonistas & inibidores , Receptores dos Hormônios Tireóideos/genética , Receptor X Retinoide beta/antagonistas & inibidores , Receptor X Retinoide beta/genética , Técnicas do Sistema de Duplo-Híbrido
14.
Cancer Invest ; 37(2): 113-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30836777

RESUMO

The 8-hydroxy-2'-deoxyguanosine (8-OHdG) damages are base damages induced by reactive oxygen species. We aimed to investigate the role of Androgen Receptor and NKX3.1 in 8-OHdG formation and repair activation by quantitating the DNA damage using Aklides.NUK system. The data demonstrated that the loss of NKX3.1 resulted in increased oxidative DNA damage and its overexpression contributes to the removal of menadione-induced 8-OHdG damage even under oxidative stress conditions. Moreover, 8-oxoguanine DNA glycosylase-1 (OGG1) expression level positively correlates to NKX3.1 expression. Also in this study, first time a reliable cell-based quantitation method for 8-OHdG damages is reported and used for data collection.


Assuntos
Dano ao DNA/genética , Proteínas de Homeodomínio/genética , Estresse Oxidativo/genética , Neoplasias da Próstata/genética , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Desoxiguanosina/genética , Genômica/métodos , Humanos , Masculino , Células PC-3 , Receptores Androgênicos/genética
15.
Int J Mol Sci ; 20(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875922

RESUMO

Spinal bulbar muscular atrophy (SBMA) is a slowly progressive, androgen-dependent neuromuscular disease in men that is characterized by both muscle and synaptic dysfunction. Because gene expression in muscle is heterogeneous, with synaptic myonuclei expressing genes that regulate synaptic function and extrasynaptic myonuclei expressing genes to regulate contractile function, we used quantitative PCR to compare gene expression in these two domains of muscle from three different mouse models of SBMA: the "97Q" model that ubiquitously expresses mutant human androgen receptor (AR), the 113Q knock-in (KI) model that expresses humanized mouse AR with an expanded glutamine tract, and the "myogenic" model that overexpresses wild-type rat AR only in skeletal muscle. We were particularly interested in neurotrophic factors because of their role in maintaining neuromuscular function via effects on both muscle and synaptic function, and their implicated role in SBMA. We confirmed previous reports of the enriched expression of select genes (e.g., the acetylcholine receptor) in the synaptic region of muscle, and are the first to report the synaptic enrichment of others (e.g., glial cell line-derived neurotrophic factor). Interestingly, all three models displayed comparably dysregulated expression of most genes examined in both the synaptic and extrasynaptic domains of muscle, with only modest differences between regions and models. These findings of comprehensive gene dysregulation in muscle support the emerging view that skeletal muscle may be a prime therapeutic target for restoring function of both muscles and motoneurons in SBMA.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular Espinal/genética , Receptores Androgênicos/genética , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Atrofia Muscular Espinal/metabolismo , Ratos , Receptores Androgênicos/metabolismo
16.
Expert Opin Investig Drugs ; 28(5): 435-443, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30897975

RESUMO

INTRODUCTION: Salivary gland cancers (SGCs) are a rare and heterogeneous group of malignant tumors arising from either major or minor salivary glands. Among SGCs patients, adenoid cystic carcinoma (ACC) is the most frequent histotype and its genetic aberrations are well known even though they are generally uncommon. Non-ACC subtypes are rarer and more heterogeneous than ACC from a histological and genomic point of view. In non-ACC, some altered molecular pathways [e.g. BRAF or RET mutations, Androgen Receptor (AR)] are potentially targetable with specific drugs. AREAS COVERED: A literature search was performed to summarize the main druggable genomic aberrations involving non-ACC SGCs. An overview of the genomics of non-ACC salivary gland malignancies is discussed. We describe the pattern of potentially targetable genomic alterations in non-ACC salivary gland malignancies according to their frequency rather than to the single non-ACC histotype. EXPERT OPINION/COMMENTARY: The genetic profiling through in-depth molecular analyses [e.g. Next-generation sequencing (NGS)] is advised in all patients affected by recurrent and/or metastatic non-ACC SGCs to find any potentially druggable target. Some histotypes may carry driving mutations that must be investigated and defined. For the rare cancers, access to a referral center is recommended to optimize the management of these patients.


Assuntos
Antineoplásicos/farmacologia , Genômica , Neoplasias das Glândulas Salivares/tratamento farmacológico , Humanos , Terapia de Alvo Molecular , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores Androgênicos/genética , Neoplasias das Glândulas Salivares/genética
17.
BMC Cancer ; 19(1): 229, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30871495

RESUMO

BACKGROUND: Prostate cancer (PCa) is the most common diagnosed malignancy and the second leading cause of cancer-related deaths among men in the United States. High-throughput genotyping has enabled discovery of germline genetic susceptibility variants (herein referred to as germline mutations) associated with an increased risk of developing PCa. However, germline mutation information has not been leveraged and integrated with information on acquired somatic mutations to link genetic susceptibility to tumorigenesis. The objective of this exploratory study was to address this knowledge gap. METHODS: Germline mutations and associated gene information were derived from genome-wide association studies (GWAS) reports. Somatic mutation and gene expression data were derived from 495 tumors and 52 normal control samples obtained from The Cancer Genome Atlas (TCGA). We integrated germline and somatic mutation information using gene expression data. We performed enrichment analysis to discover molecular networks and biological pathways enriched for germline and somatic mutations. RESULTS: We discovered a signature of 124 genes containing both germline and somatic mutations. Enrichment analysis revealed molecular networks and biological pathways enriched for germline and somatic mutations, including, the PDGF, P53, MYC, IGF-1, PTEN and Androgen receptor signaling pathways. CONCLUSION: Integrative genomic analysis links genetic susceptibility to tumorigenesis in PCa and establishes putative functional bridges between the germline and somatic variation, and the biological pathways they control.


Assuntos
Biomarcadores Tumorais/genética , Redes Reguladoras de Genes , Genômica/métodos , Mutação , Neoplasias da Próstata/genética , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Humanos , Fator de Crescimento Insulin-Like I/genética , Masculino , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptores Androgênicos/genética , Proteína Supressora de Tumor p53/genética
18.
J Cancer Res Ther ; 15(Supplement): S60-S68, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30900623

RESUMO

Objective: To estimate association between androgen receptor (AR) gene polymorphisms and testicular germ cell tumor (TGCT) susceptibility. Materials and Methods: Systematic search of studies on the association between AR gene polymorphisms and TGCT susceptibility was conducted. Odds ratios and 95% confidence intervals were used to pool effect size. Results: For CAG repeat, no evidence was found for association between (>25 vs. ≤25), (>25 vs. 21-25), (<21 vs. 21-25), (others vs. 21-25), (>23 vs. ≤23), (<21 vs. ≥21), (<21 vs. ≥21)'s some subgroups and TGCT susceptibility, which showed stability. In (>24 vs. ≤24), (>24 vs. 21-24), (<21 vs. 21-24), and (others vs. 21-24) and almost all of their subgroups, increased TGCT risk was found without sensitivity analysis. For GGN, no statistical change of TGCT risk was found in (<23 vs. ≥23), (<23 vs. 23), which showed stability. For single nucleotide polymorphism (SNP) rs6152 G > A, rs1204038 G > A and rs2361634 A > G, no statistical change was found without sensitivity analysis. Conclusions: GGN repeat number <23 may not be associated with TGCTs susceptibility. However, there was insufficient data to fully confirm association in GGN repeat number >23, CAG repeat number, SNP rs6152, rs1204038, and rs2361634.


Assuntos
Predisposição Genética para Doença , Neoplasias Embrionárias de Células Germinativas/genética , Receptores Androgênicos/genética , Neoplasias Testiculares/genética , Repetições de Trinucleotídeos/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
19.
Int J Mol Sci ; 20(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925701

RESUMO

Canine carcinomas have been considered natural models for human diseases; however, the genomic profile of canine prostate cancers (PCs) has not been explored. In this study, 14 PC androgen-receptor-negative cases, 4 proliferative inflammatory atrophies (PIA), and 5 normal prostate tissues were investigated by array-based comparative genomic hybridization (aCGH). Copy number alterations (CNAs) were assessed using the Canine Genome CGH Microarray 4 × 44K (Agilent Technologies). Genes covered by recurrent CNAs were submitted to enrichment and cross-validation analysis. In addition, the expression levels of TP53, MDM2 and ZBTB4 were evaluated in an independent set of cases by qPCR. PC cases presented genomic complexity, while PIA samples had a small number of CNAs. Recurrent losses covering well-known tumor suppressor genes, such as ATM, BRCA1, CDH1, MEN1 and TP53, were found in PC. The in silico functional analysis showed several cancer-related genes associated with canonical pathways and interaction networks previously described in human PC. The MDM2, TP53, and ZBTB4 copy number alterations were translated into altered expression levels. A cross-validation analysis using The Cancer Genome Atlas (TCGA) database for human PC uncovered similarities between canine and human PCs. Androgen-receptor-negative canine PC is a complex disease characterized by high genomic instability, showing a set of genes with similar alterations to human cancer.


Assuntos
Doenças do Cão/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/veterinária , Receptores Androgênicos/genética , Transcriptoma , Animais , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Cães , Instabilidade Genômica , Genômica , Masculino , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética
20.
In Vivo ; 33(2): 447-452, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30804124

RESUMO

BACKGROUND: To analyze for genetic mutations which may presage peritoneal metastasis by using targeted next-generation sequencing (NGS). MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded primary tumor specimens were obtained from 10 patients with small obstructing colorectal cancer and peritoneal metastasis (group A) and five with large non-obstructing colorectal cancer and no recurrence (group B). DNA was extracted for the sequencing of 409 cancer genes. The distribution of genetic mutations was compared between the two groups to find genetic mutations related to peritoneal metastasis. RESULTS: When the samples were sorted based on similarity of gene expression by hierarchical clustering analysis, the samples were well divided between the two study groups. Mutations in AT-rich interactive domain-containing protein 1A (ARID1A), polycystic kidney and hepatic disease 1 (PKHD1), ubiquitin-protein ligase E3 component n-recognin 5 (UBR5), paired box 5 (PAX5), tumor protein p53 (TP53), additional sex combs like 1 (ASXL1) and androgen receptor (AR) genes were detected more frequently in group A. CONCLUSION: A number of somatic mutations presumed to be relevant to colorectal cancer with peritoneal metastasis were identified in our study by NGS.


Assuntos
Neoplasias Colorretais/genética , Mutação/genética , Recidiva Local de Neoplasia/genética , Neoplasias Peritoneais/genética , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Proteínas Nucleares/genética , Fator de Transcrição PAX5/genética , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Receptores Androgênicos/genética , Receptores de Superfície Celular/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA