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1.
J Urol ; 203(2): 350, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31674872
2.
J Urol ; 203(2): 344-350, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31502941

RESUMO

PURPOSE: Few groups have investigated the combined effects of PTEN loss and ERG expression on the outcomes of metastasis of or death from prostate cancer in surgically treated patients. We examined the association of PTEN/ERG status with lethal prostate cancer in patients treated with radical prostatectomy. MATERIALS AND METHODS: Included in analysis were 791 patients with clinically localized prostate cancer treated with radical prostatectomy at a single institution. Genetically validated immunohistochemistry assays for PTEN and ERG were performed on tissue microarrays. Multivariable Cox proportional hazard models were used to assess the association of PTEN/ERG status with lethal prostate cancer (defined as metastasis or prostate cancer specific death), adjusting for patient age, race, pathological grade and stage, and surgical margin status. RESULTS: Median followup in the cohort was 12.8 years. Of 791 cases 203 (25%) demonstrated PTEN loss and 330 of 776 (43%) were ERG positive. On multivariable analysis PTEN loss (HR 1.9, 95% CI 1.2-3.0, p=0.012) but not ERG expression (HR 0.6, 95% CI 0.4-1.1, p=0.11) was associated with an increased risk of lethal prostate cancer. The association of PTEN loss with lethal disease only remained among men with ERG negative tumors (HR 2.3, 95% CI 1.3-4.1, p=0.005) and not ERG positive tumors (HR 1.1, 95% CI 0.6-2.1, p=0.81). CONCLUSIONS: PTEN loss is associated with an increased risk of lethal prostate cancer after radical prostatectomy and this risk is most pronounced in the subgroup of patients with ERG negative tumors. This work corroborates the use of PTEN and ERG status for risk stratification in surgically treated patients.


Assuntos
PTEN Fosfo-Hidrolase/análise , Prostatectomia , Neoplasias da Próstata/química , Neoplasias da Próstata/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prostatectomia/métodos , Regulador Transcricional ERG/análise , Resultado do Tratamento
3.
Braz J Med Biol Res ; 52(12): e8483, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31826177

RESUMO

PTEN is the most commonly inactivated tumor suppressor gene in primary prostate cancer (PCa) and its loss is associated with poor clinical outcomes. ERG rearrangement is a genomic alteration frequently found in PCa and its prognostic significance has yielded mixed results. Although the association of PTEN and ERG biomarkers has potential impact on clinical outcomes, studies examining the two genes simultaneously are scarce in Brazilian populations. In this study, we retrospectively examined the relationship between ERG expression and PTEN loss in 119 surgically treated prostate cancer patients from Northeastern Brazil through immunohistochemical analysis. ERG expression was found in 41.0% (48/117) of cases and the loss of PTEN detected in 38.1% (40/105) of samples. ERG-positive cases were significantly associated with lower prostate weight; ERG negatively correlated with Gleason score above 6. The lack of associations for PTEN loss alone in this cohort is counter to the literature, which shows that PTEN loss is usually associated with more aggressive disease. The overlapping of the two biomarkers revealed that samples with positive ERG expression without PTEN loss were associated with lower Gleason and lower Grade group. This study contributes with the discussion about the development of the molecular profiling of prostate cancer. The further development of similar studies could help in stratifying specific risk groups, leading to a more personalized therapeutic decision for prostate cancer treatment.


Assuntos
Regulação Neoplásica da Expressão Gênica , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , PTEN Fosfo-Hidrolase/sangue , PTEN Fosfo-Hidrolase/genética , Prevalência , Prognóstico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Regulador Transcricional ERG/sangue , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo
4.
BMC Cancer ; 19(1): 972, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31638934

RESUMO

BACKGROUND: Castrate Resistant Prostate Cancer (CRPC) is an advanced disease resistant to systemic traditional medical or surgical castration, and resistance is primarily attributed to reactivation of AR through multiple mechanisms. TMPRSS2-ERG fusions have been shown to regulate AR signaling, interfere with pro-differentiation functions, and mediate oncogenic signaling. We have recently shown that ERG regulates intra-tumoral androgen synthesis and thereby facilitates AR function in prostate cancer cells. We hypothesize that enzalutamide treatment will be more effective in cells/tumors with TMPRSS2-ERG translocations because these tumors have increased AR signaling. METHODS: ERG knockdown was performed with VCaP cells using lentiviral infections to generate VCaP ERGshRNA cells and control VCaP scr cells with scrambled shRNA. Cell-growth analysis was performed to determine the effect of enzalutamide. Reverse transcription, quantitative real-time PCR (RT-qPCR) was used to determine the expression of AR responsive genes. Luciferase tagged VCaP scr and shRNA infected cells were used in an intra-tibial animal model for bone tumor growth analysis and enzalutamide treatment used to inhibit AR signaling in bone tumors. Western blotting analyzed VCaP bone tumor samples for ERG, AR, AKR1C3 and HSD3B1 and HSD3B2 expression. RESULTS: Enzalutamide inhibited the growth of VCaP scr cells more effectively than shERG cells. Analysis of AR responsive genes shows that Enzalutamide treatment at 5 micromolar concentration inhibited by 85-90% in VCaP Scr cells whereas these genes were inhibited to a lesser extent in VCaP shERG cells. Enzalutamide treatment resulted in severe growth inhibition in VCaP scr shRNA cells compared to VCaP shERG cells. In bone tumor growth experiment, VCaP ERG shRNA cells grew at slower than VCaP scr shRNA cells. Androgen biosynthetic enzyme expression is lower VCaP shERG bone tumors compared to VCaP scr shRNA bone tumors and enzalutamide inhibited the enzyme expression in both types of tumors. CONCLUSIONS: These data suggest that ERG transcription factor regulates androgen biosynthetic enzyme expression that enzalutamide treatment is more effective against VCaP bone tumors with an intact ERG expression, and that knocking down ERG in VCaP cells leads to a lesser response to enzalutamide therapy. Thus, ERG expression status in tumors could help stratify patients for enzalutamide therapy.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Feniltioidantoína/análogos & derivados , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Animais , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos SCID , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
5.
BMC Cancer ; 19(1): 944, 2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31606028

RESUMO

BACKGROUND: Protein tyrosine phosphatase non-receptor 12 (PTPN12) is ubiquitously tyrosine phosphatase with tumor suppressive properties. METHODS: PTPN12 expression was analyzed by immunohistochemistry on a tissue microarray with 13,660 clinical prostate cancer specimens. RESULTS: PTPN12 staining was typically absent or weak in normal prostatic epithelium but seen in the majority of cancers, where staining was considered weak in 26.5%, moderate in 39.9%, and strong in 4.7%. High PTPN12 staining was associated with high pT category, high classical and quantitative Gleason grade, lymph node metastasis, positive surgical margin, high Ki67 labeling index and early prostate specific antigen recurrence (p < 0.0001 each). PTPN12 staining was seen in 86.4% of TMPRSS2:ERG fusion positive but in only 58.4% of ERG negative cancers. Subset analyses discovered that all associations with unfavorable phenotype and prognosis were markedly stronger in ERG positive than in ERG negative cancers but still retained in the latter group. Multivariate analyses revealed an independent prognostic impact of high PTPN12 expression in all cancers and in the ERG negative subgroup and to a lesser extent also in ERG positive cancers. Comparison with 12 previously analyzed chromosomal deletions revealed that high PTPN12 expression was significantly associated with 10 of 12 deletions in ERG negative and with 7 of 12 deletions in ERG positive cancers (p < 0.05 each) indicating that PTPN12 overexpression parallels increased genomic instability in prostate cancer. CONCLUSIONS: These data identify PTPN12 as an independent prognostic marker in prostate cancer. PTPN12 analysis, either alone or in combination with other biomarkers might be of clinical utility in assessing prostate cancer aggressiveness.


Assuntos
Neoplasias da Próstata/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 12/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Deleção Cromossômica , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Proteínas de Fusão Oncogênica/metabolismo , Células PC-3 , Prognóstico , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Receptor ErbB-2/metabolismo , Análise Serial de Tecidos , Regulador Transcricional ERG/metabolismo
6.
Prostate ; 79(14): 1640-1646, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31376218

RESUMO

BACKGROUND: There are no comparative data on pathological predictors at diagnosis, between African Caribbean and Caucasian men with prostate cancer (PCa), in equal-access centers. The objective of this study was to evaluate the grade groups of an African Caribbean cohort, newly diagnosed with PCa on prostate biopsy, compared with a Caucasian French Metropolitan cohort. METHODS: A retrospective, a comparative study was conducted between 2008 and 2016 between the University Hospital of Martinique in the French Caribbean West Indies, and the Saint Joseph Hospital in Paris. Clinical, biological, and pathological data were collected at diagnosis. The primary outcome was the grade groups for Gleason score; the secondary outcome was the PCa detection rate. Multivariate analysis was performed using linear regression. RESULTS: Of the 1880 consecutive prostate biopsy performed in the African Caribbean cohort, 945 had a diagnosis of PCa (50.3%) and 500 of 945 in the French cohort (33.8%). African Caribbean patients were older (mean 68.5 vs 67.5 years; P = .028), had worse clinical stage (13.2% vs 5.2% cT3-4; P < .001) and higher median prostate-specific antigen (PSA) level (9.23 vs 8.32 ng/mL; P = .019). On univariate analysis, African Caribbean patients had worse pathological grade groups than French patients (P < .001). Nevertheless, after adjustment on age, stage, and PSA, there were no significant differences between the two cohorts (P = .903). CONCLUSION: African Caribbean patients presented higher PCa detection rate, and higher grade groups at diagnosis than French patients in equal-access centers on univariate analysis but not on multivariate analysis. African Caribbean patients with equivalent clinical and biological characteristics than Caucasian patients at diagnosis might expect the same prognosis for PCa.


Assuntos
Grupo com Ancestrais do Continente Africano , Neoplasias da Próstata/patologia , Idoso , Biópsia , Grupo com Ancestrais do Continente Europeu , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Paris , Prognóstico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/química , Estudos Retrospectivos , Fatores de Risco , Regulador Transcricional ERG/análise , Índias Ocidentais
7.
PLoS Genet ; 15(8): e1008288, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393878

RESUMO

Neuronal physiology is particularly sensitive to acute stressors that affect excitability, many of which can trigger seizures and epilepsies. Although intrinsic neuronal homeostasis plays an important role in maintaining overall nervous system robustness and its resistance to stressors, the specific genetic and molecular mechanisms that underlie these processes are not well understood. Here we used a reverse genetic approach in Drosophila to test the hypothesis that specific voltage-gated ion channels contribute to neuronal homeostasis, robustness, and stress resistance. We found that the activity of the voltage-gated potassium channel seizure (sei), an ortholog of the mammalian ERG channel family, is essential for protecting flies from acute heat-induced seizures. Although sei is broadly expressed in the nervous system, our data indicate that its impact on the organismal robustness to acute environmental stress is primarily mediated via its action in excitatory neurons, the octopaminergic system, as well as neuropile ensheathing and perineurial glia. Furthermore, our studies suggest that human mutations in the human ERG channel (hERG), which have been primarily implicated in the cardiac Long QT Syndrome (LQTS), may also contribute to the high incidence of seizures in LQTS patients via a cardiovascular-independent neurogenic pathway.


Assuntos
Proteínas de Drosophila/genética , Resposta ao Choque Térmico/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Convulsões/genética , Regulador Transcricional ERG/genética , Animais , Animais Geneticamente Modificados , Drosophila , Proteínas de Drosophila/metabolismo , Técnicas de Silenciamento de Genes , Incidência , Síndrome do QT Longo/complicações , Síndrome do QT Longo/genética , Neurônios/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Genética Reversa , Convulsões/epidemiologia , Regulador Transcricional ERG/metabolismo
8.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295848

RESUMO

Human ether a-go-go related gene (hERG) or KV11.1 potassium channels mediate the rapid delayed rectifier current (IKr) in cardiac myocytes. Drug-induced inhibition of hERG channels has been implicated in the development of acquired long QT syndrome type (aLQTS) and fatal arrhythmias. Several marketed drugs have been withdrawn for this reason. Therefore, there is considerable interest in developing better tests for predicting drugs which can block the hERG channel. The drug-binding pocket in hERG channels, which lies below the selectivity filter, normally contains K+ ions and water molecules. In this study, we test the hypothesis that these water molecules impact drug binding to hERG. We developed 3D QSAR models based on alignment independent descriptors (GRIND) using docked ligands in open and closed conformations of hERG in the presence (solvated) and absence (non-solvated) of water molecules. The ligand-protein interaction fingerprints (PLIF) scheme was used to summarize and compare the interactions. All models delineated similar 3D hERG binding features, however, small deviations of about ~0.4 Å were observed between important hotspots of molecular interaction fields (MIFs) between solvated and non-solvated hERG models. These small changes in conformations do not affect the performance and predictive power of the model to any significant extent. The model that exhibits the best statistical values was attained with a cryo_EM structure of the hERG channel in open state without water. This model also showed the best R2 of 0.58 and 0.51 for the internal and external validation test sets respectively. Our results suggest that the inclusion of water molecules during the docking process has little effect on conformations and this conformational change does not impact the predictive ability of the 3D QSAR models.


Assuntos
Antineoplásicos/química , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Água/química , Antineoplásicos/farmacologia , Humanos , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Solubilidade , Regulador Transcricional ERG/antagonistas & inibidores , Regulador Transcricional ERG/química , Fluxo de Trabalho
9.
Tumour Biol ; 41(7): 1010428318824815, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31296150

RESUMO

GATA2 is a pioneering transcription factor governing androgen receptor expression and signaling in prostate cells. To understand the prognostic potential of GATA2 assessment in prostate cancer, we analyzed nuclear GATA2 expression on an annotated tissue microarray with 12,427 prostate cancer samples. Normal prostate glands were negative to weakly positive. GATA2 staining was found in almost all prostate cancers (95%). Strong GATA2 staining was linked to advanced tumor stage, high classical and quantitative Gleason grade (p < 0.0001 each), positive nodal stage (p = 0.0116), and early biochemical recurrence (p < 0.0001). GATA2 was linked to ERG-fusion-type cancers, with strong GATA2 staining in 29% of ERG-negative and 53% of ERG-positive cancers (p < 0.0001). Separate calculations in 3854 cancers with and 4768 cancers without TMPRSS2:ERG fusion revealed that these associations with tumor phenotype and patient outcome were largely driven by the subset of ERG-negative tumors. GATA2 expression was further linked to androgen receptor expression: Only 8% of androgen receptor-negative, but 56% of strongly androgen receptor expressing cancers had strong GATA2 expression (p < 0.0001). In conclusion, the results of our study demonstrate that increasing GATA2 levels are linked to prostate cancer progression and aggressiveness. The prognostic value of GATA2 is remarkable in ERG-negative cancers. However, the upregulation of GATA2 in ERG-positive cancers makes it unsuitable as a prognostic marker in this patient subset.


Assuntos
Fator de Transcrição GATA2/metabolismo , Neoplasias da Próstata/metabolismo , Adulto , Idoso , Progressão da Doença , Intervalo Livre de Doença , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Recidiva Local de Neoplasia , Fenótipo , Prognóstico , Prostatectomia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Análise Serial de Tecidos , Regulador Transcricional ERG/metabolismo , Resultado do Tratamento
10.
Regul Toxicol Pharmacol ; 108: 104433, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31362032

RESUMO

PF614, a novel trypsin activated abuse protection (TAAP) prodrug of oxycodone, is being studied as chronic pain analgesic with extended release and abuse resistant properties. A series of nonclinical safety studies were conducted to support PF614 introduction to clinical trials. Ames assays (PF614 and its metabolites), comet assay (PF614 ≤ 50 mg/kg/day oral gavage in rats) and micronucleus assay (PF614 ≤ 175 mg/kg/day oral gavage in rats) were negative. hERG assay IC50 for PF614 was ≥300 µM. PF614 (0.1 and 10 µM) showed a low permeability in Caco-2 cells (≤1.17 x 10-6 cm/s) and was not a P-gp or BCRP substrate or inhibitor. The mean percent unbound PF614 among all concentrations in plasma ranged from 91.2 to 98.4, 79.4 to 100, and 52.9-79.9% in rat, dog, and human, respectively. Also, PF614 was metabolically stable in rat, dog, and human hepatocytes with no metabolites identified. Safety pharmacology study in dog indicated moderately lower heart rate at ≥ 2 mg/kg oral gavage doses. Toxicity studies of PF614 in rat and dog with daily oral doses of 25 and 18 mg/kg, respectively, for 14 Days were well tolerated with favorable safety profile supporting its further clinical evaluation.


Assuntos
Formulações de Dissuasão de Abuso , Analgésicos Opioides/toxicidade , Oxicodona/toxicidade , Pró-Fármacos/toxicidade , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Células CACO-2 , Cães , Eletrocardiografia/efeitos dos fármacos , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Masculino , Testes de Mutagenicidade , Proteínas de Neoplasias/metabolismo , Ratos , Regulador Transcricional ERG/metabolismo , Tripsina
11.
Plast Reconstr Surg ; 144(2): 372-384, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31348346

RESUMO

BACKGROUND: We investigated expression of prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 by the embryonic stem cell-like population on the endothelium of the microvessels and perivascular cells within keloid-associated lymphoid tissues. METHODS: Immunohistochemical staining for prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 was performed on 11 formalin-fixed, paraffin-embedded sections of keloid tissue samples. Immunofluorescence staining was performed on three keloid tissue samples by co-staining with OCT4, CD34, ERG, and tryptase. Real-time quantitative polymerase chain reaction was performed on five keloid tissue samples and four keloid-derived primary cell lines. Western blotting was performed on the four keloid-derived primary cell lines for mRNA and protein expression of these proteins, respectively. RESULTS: Immunohistochemical and immunofluorescence staining showed expression of prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 in all 11 keloid tissue samples. Prorenin receptor and angiotensin II receptor 1 were expressed on the endothelium and the pericyte layer of the microvessels and perivascular cells, angiotensin II receptor 2 was localized to the endothelium of the microvessels and the tryptase-positive perivascular cells, and angiotensin-converting enzyme was localized to the endothelium of the microvessel, within the keloid-associated lymphoid tissues. Real-time quantitative polymerase chain reaction showed transcripts of prorenin receptor, angiotensin-converting enzyme, and angiotensin II receptor 1 in the keloid tissue samples and keloid-derived primary cell lines, whereas angiotensin II receptor 2 was detected in keloid tissue samples only. Western blotting confirmed the presence of prorenin receptor, angiotensin-converting enzyme, and angiotensin II receptor 1 in the keloid-derived primary cell lines. CONCLUSION: Prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 were expressed by the embryonic stem cell-like population within the keloid-associated lymphoid tissues, suggesting that this primitive population may be a potential therapeutic target by modulation of the renin-angiotensin system.


Assuntos
Células-Tronco Embrionárias/metabolismo , Queloide/metabolismo , Sistema Renina-Angiotensina/fisiologia , Adolescente , Adulto , Antígenos CD34/metabolismo , Linhagem Celular , Criança , Pré-Escolar , Feminino , Imunofluorescência , Humanos , Queloide/patologia , Masculino , Pessoa de Meia-Idade , Fator 3 de Transcrição de Octâmero/metabolismo , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores de Superfície Celular/metabolismo , Regulador Transcricional ERG/metabolismo , Adulto Jovem
12.
Curr Pharm Des ; 25(12): 1385-1391, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218953

RESUMO

BACKGROUND: As2O3 and resveratrol have been widely considered to be effective in anti-cancer therapies and the underlying mechanisms have been reported extensively. However, the combined treatment effect and potential target of As2O3 and resveratrol in the treatment of tumors remains elusive. The purpose of this study was to investigate the benefits and efficacy of As2O3 in combination with resveratrol in the treatment of colon cancer, as well as looking for new targets that could provide alternative explanation of the efficacy of drugs. METHODS: The proliferation of cancer cells was measured by the MTT and EdU staining assay, while the apoptosis of cancer cells was determined by the flow cytometry. Western blot and immunoprecipitation were performed to measure the expression levels of proteins and the interaction between hERG and integrin ß1, respectively. RESULTS: In this study, we found that both As2O3 and resveratrol can effectively inhibit cell proliferation and promote cell apoptosis in colon cancer, and the combined effect of the two drugs on colon cancer cells is more preeminent. The combination of As2O3 with resveratrol, on the one hand reduced the expression of hERG channels on the membrane, and on the other hand weaken the binding between hERG and integrin ß 1, which may be the main cause of downstream signaling pathways alterations, including the activation of the apoptotic pathway. CONCLUSION: Taken together, hERG, as a subunit of potassium ion channel on the cell membrane, is highly likely to be involved in the As2O3 and resveratrol induced intracellular signaling cascade disorder, and this novel signaling pathway that sustains the progression of colon cancer may be a promising therapeutic target for human colon cancer treatment in the future.


Assuntos
Apoptose , Trióxido de Arsênio/farmacologia , Proliferação de Células , Neoplasias do Colo/patologia , Resveratrol/farmacologia , Antineoplásicos , Arsenicais , Linhagem Celular Tumoral , Humanos , Óxidos , Transdução de Sinais , Regulador Transcricional ERG/metabolismo
13.
Mol Carcinog ; 58(10): 1846-1854, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31237044

RESUMO

ERG (avian v-ets erythroblastosis virus E26 oncogene homolog), an oncoprotein in prostate carcinoma and Ewing's sarcoma is associated with poor prognosis in patients with acute myeloid leukemia and T lymphoblastic leukemia. However little is known about ERG in lymphoma. Here we studied ERG in diffuse large B-cell lymphoma (DLBCL) by immunohistochemistry, fluorescence in situ hybridization (FISH), genome-wide microRNA (miRNA) expression profiling, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and whole exome sequencing (WES). Approximately 30% of de novo DLBCLs (37 of 118) expressed ERG (ERG+). ERG expression showed no significant correlation with DLBCL cell-of-origin classification, patient's age, sex, nodal, or extranodal disease status, tumor expression of p53 or p63. There was no ERG rearrangement in 10 randomly selected ERG+ DLBCLs by FISH. Forty-three miRNAs showed significant differential expression between ERG+ and ERG- DLBCLs. Downregulation of miR-4638-5p was confirmed by real-time RT-PCR. WES not only confirmed known gene mutations in DLBCLs but also revealed multiple novel gene mutations in POLA1, E2F1, PSMD8, AXIN1, GAB2, and GNB2L1, which occur more frequently in ERG+ DLBCLs. In conclusion, our studies demonstrated aberrant ERG expression in a subset of DLBCL, which is associated with downregulation of miR-4638-5p. In comparison with ERG-negative DLBCL, ERG+ DLBCL more likely harbors mutations in genes important in cell cycle control, B-cell receptor-mediated signaling and degradation of ß-catenin. Further clinicopathological correlation and functional studies of ERG-related miRNAs and pathways may provide new insight into the pathogenesis of DLBCL and reveal novel targets for better management of patients with DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B/genética , MicroRNAs/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Prognóstico , Transdução de Sinais/genética , Regulador Transcricional ERG/genética , Sequenciamento Completo do Exoma
14.
Virchows Arch ; 475(2): 223-231, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31209634

RESUMO

The role of DNA MMR genes in prostate cancer (PrCa) is controversial, as genetic alterations leading to microsatellite instability are incompletely defined in these tumors. ERG rearrangements and PTEN loss are concomitant events in PrCa. The aim of this study has been to analyze the immunohistochemical (IHC) expression of MSH2, MSH6, MLH1, PMS2, ERG, and PTEN and their potential association with the grade group (GG) grading system (WHO 2016) and PSA recurrence in a series of 200 PrCa (PSMAR-Biobank, Barcelona, Spain). MSH2, MLH1, PMS2, and PTEN losses were documented in 8%, 5%, 2%, and 36.5%, respectively. ERG expression was found in 48%. MSH6 showed an increase of expression with respect to basal levels in 42.1% of the cases. A statistical association between MSH6 overexpression and GG5 was found (p = 0.0281). ERG-wild-type cases were associated with single MSH2 loss (p = 0.024), and MSH2 and/or MLH1 loss (p = 0.019). The percentage of cases with PTEN loss was 20.5% (8/39) in GG1, 37.6% (53/141) of clustered GG2 to 4, and 60% (12/20) of GG5 (chi-square test, p = 0.01). Thus, PTEN expression loss was statistically more frequent in the upper-grade tumors. PMS2 loss was an infrequent event, but it was statistically associated with shorter time to PSA recurrence (p = 0.011). These results suggest the existence of an alternative non-ERG pathway associated with MSH2 or MLH1 expression loss. MSH6 overexpression could be a marker of aggressiveness in PrCa. The IHC assessment of DNA MMR proteins, ERG and PTEN, could identify different altered PrCa pathways, which could aid patient stratification.


Assuntos
Biomarcadores Tumorais/análise , Reparo de Erro de Pareamento de DNA/fisiologia , PTEN Fosfo-Hidrolase/biossíntese , Neoplasias da Próstata/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/metabolismo , Regulador Transcricional ERG/biossíntese
15.
Prostate ; 79(11): 1274-1283, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31111520

RESUMO

BACKGROUND: Expression of p16 is increased in a number of malignancies, including prostate cancer (PCa). Recent studies in a European cohort showed that expression of p16 is correlated with expression of the TMPRSS2/ERG (T/E) fusion protein. The T/E fusion is significantly less common in PCas in African American (AA) men. Thus, it would be predicted that p16 expression should be less common in PCas in AA men. We, therefore, sought to compare the expression of p16 in benign prostate and PCas from AA and European American (EA) men. METHODS: Immunohistochemistry for p16 and ERG was performed on tissue microarrays constructed from radical prostatectomies performed on AA and EA veterans. Staining was scored and the scores compared with demographic, clinical and pathological parameters. Percent of West African ancestry in the AA cohort was assessed using ancestry informative markers. RESULTS: Contrary to our predictions, p16 expression was similar in the cancers in the AA and EA cohorts. Consistent with prior reports, expression of p16 was quite low in benign prostate tissues from EA patients but surprisingly was significantly higher in benign tissues from AA patients. Expression of p16 was significantly associated with a family history of PCa in AA men. In addition, p16 was associated with ERG expression in AA PCa. CONCLUSIONS: While overall expression of p16 is similar in PCas from the two racial groups, the expression of p16 in benign tissues from a subset of AA men and the stronger correlation with ERG expression implies that there are different mechanisms for p16 overexpression in PCas from the two racial groups.


Assuntos
Afro-Americanos , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Grupo com Ancestrais do Continente Europeu , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Neoplasias da Próstata/patologia , Análise Serial de Tecidos , Regulador Transcricional ERG/metabolismo
16.
Prostate ; 79(10): 1156-1165, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31090082

RESUMO

BACKGROUND: ERG fusion-related prostate cancer (PrCa) is the most prevalent oncogenic driver subclass. SPOP, FOXA1, and IDH1 mutations are other three main oncogenic driver subclasses in non-ETS-fusion PrCa. ERG protein levels seem to be increased in SPOP-mutated cases, and different studies reported that SPOP mutations and ERG fusions are mutually exclusive. The aim of this study has been to analyze the alterations in non-ETS-oncogenic drivers in PrCa. METHODS: SPOP, FOXA1, and IDH mutations were investigated by polymerase chain reaction (PCR) and Sanger direct sequencing. ERG, SPOP, and TMPRSS2-ERG messenger RNA expression was assessed by quantitative real-time PCR from complementary DNA, and the presence of the fusion was also analyzed by nonquantitative PCR. The clinical pathological features were retrieved from the charts of the 111 patients included in the study (MARBiobanc, Barcelona, Spain). RESULTS: Loss of SPOP expression (25.2%) was associated with ERG overexpression (P = 0.0036). SPOP mutations were found in 5.4% cases, all with wild-type (wt) ERG (P = 0.007). FOXA1 mutations were found in 8.2% cases, most of them ERG wt (P = 0.06). No IDH1 mutations were found. SPOP or FOXA1 mutations were found in 1.7% of ERG-rearranged, and 34.2% of non-ERG-rearranged cases (P < 0.0001). SPOP or FOXA1 alterations (mutations or expression loss) were significantly more common in GG5, while isolated ERG overexpression was more common in GG1 tumors (P = 0.042). SPOP-or FOXA1-mutated cases were associated with a shorter time to prostate-specific antigen (PSA) recurrence in the univariate (P = 0.0009), and with the PSA recurrence risk in the multivariate (P = 0.023) analysis. CONCLUSIONS: In conclusion, SPOP and FOXA1 mutations may have prognostic value in ERG wt tumors. Interestingly, in absence of SPOP mutations, downregulation of this gene is a feature of many ERG-rearranged prostate tumors.


Assuntos
Fator 3-alfa Nuclear de Hepatócito/genética , Recidiva Local de Neoplasia/genética , Proteínas Nucleares/genética , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/genética , Proteínas Repressoras/genética , Idoso , Biomarcadores Tumorais/sangue , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Regulador Transcricional ERG/genética
17.
Prostate ; 79(10): 1191-1196, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31090091

RESUMO

BACKGROUND: The androgen-regulated gene TMPRSS2 to the ETS transcription factor gene ERG fusion is the most common genomic alteration acquired during prostate tumorigenesis and biased toward men of European ancestry. In contrast, African American men present with more advanced disease, yet their tumors are less likely to acquire TMPRSS2-ERG. Data for Africa is scarce. METHODS: RNA was made available for genomic analyses from 181 prostate tissue biopsy cores from Black South African men, 94 with and 87 without pathological evidence for prostate cancer. Reverse transcription polymerase chain reaction was used to screen for the TMPRSS2-ERG fusion, while transcript junction coordinates and isoform frequencies, including novel gene fusions, were determined using targeted RNA sequencing. RESULTS: Here we report a frequency of 13% for TMPRSS2-ERG in tumors from Black South Africans. Present in 12/94 positive versus 1/87 cancer negative prostate tissue cores, this suggests a 92.62% predictivity for a positive cancer diagnosis (P = 0.0031). At a frequency of almost half that reported for African Americans and roughly a quarter of that reported for men of European ancestry, acquisition of TMPRSS2-ERG appears to be inversely associated with aggressive prostate cancer. Further support was provided by linking the presence of TMPRSS2-ERG to low-grade disease in younger patients (P = 0.0466), with higher expressing distal ERG fusion junction coordinates. CONCLUSIONS: Only the second study of its kind for the African continent, we support a link between TMPRSS2-ERG status and prostate cancer racial health disparity beyond the borders of the United States. We call for urgent evaluation of androgen deprivation therapy within Africa.


Assuntos
Fusão Oncogênica/genética , Neoplasias da Próstata/genética , Serina Endopeptidases/genética , Adulto , Grupo com Ancestrais do Continente Africano , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Europeu , Instabilidade Genômica , Disparidades nos Níveis de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Neoplasias da Próstata/patologia , África do Sul , Regulador Transcricional ERG/genética
18.
J Nippon Med Sch ; 86(2): 126-130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31130564

RESUMO

Pseudomyogenic hemangioendothelioma (PMHE) is a new entity. It is an intermediate soft tissue tumor clinically and/or histopathologically mimicking some other high-grade malignant tumors and some inflammatory diseases. We report a case of PMHE on the left plantar surface of a 28-year-old woman. Histopathological examination of the resected specimen revealed spindle and epithelioid cells with plump and atypical nuclei proliferated in the dermis and subcutaneous fat tissue with marked fibroplasia. Both spindle and epithelioid cells had abundant eosinophilic cytoplasm. Neoplastic cells were diffusely positive for AE1/AE3, CK7, vimentin, CD31, FLI-1, ERG, and INI-1. From those findings, we made the diagnosis of PMHE. We describe the main points of differentiation between PMHE and diseases that have similar clinical and/or histopathological findings, including cellular dermatofibroma, spindle cell squamous cell carcinoma, epithelioid sarcoma, epithelioid hemangioendothelioma, epithelioid angiosarcoma, nodular or proliferative fasciitis, and granulomatous fibrosing granulation tissue due to a ruptured epidermal cyst.


Assuntos
Hemangioendotelioma Epitelioide/patologia , Neoplasias de Tecidos Moles/patologia , Adulto , Antiporters/metabolismo , Diagnóstico Diferencial , Feminino , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Humanos , Queratinas/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína SMARCB1/metabolismo , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/genética , Regulador Transcricional ERG/metabolismo , Vimentina/metabolismo
19.
J Cutan Pathol ; 46(7): 532-537, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30950098

RESUMO

Dermatofibrosarcoma protuberans (DFSP) is a translocation-associated, low-grade sarcoma with fibroblastic differentiation. It is the most common superficial sarcoma, almost exclusively arising within the dermis. In a minority of cases, there is a transition from the conventional morphology to a fibrosarcomatous pattern, known as a fibrosarcomatous DFSP (FS-DFSP). Although a number of different molecular alterations have been described to account for this transformation, it remains poorly understood. Herein we report the first case of a FS-DFSP with a fusion between ERG, an ETS family transcription factor, and MAP3K7CL, a kinase gene rarely observed in fusion gene events.


Assuntos
Transformação Celular Neoplásica , Dermatofibrossarcoma , Proteínas de Fusão Oncogênica , Proteínas Quinases , Neoplasias Cutâneas , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Dermatofibrossarcoma/genética , Dermatofibrossarcoma/metabolismo , Dermatofibrossarcoma/patologia , Feminino , Humanos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo
20.
Int J Mol Sci ; 20(5)2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30818754

RESUMO

This study aimed to validate whether 5-hydroxymethylcytosine (5hmC) level in combination with ERG expression is a predictive biomarker for biochemical failure (BF) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa). The study included 592 PCa patients from two consecutive Danish RP cohorts. 5hmC level and ERG expression were analyzed using immunohistochemistry in RP specimens. 5hmC was scored as low or high and ERG was scored as negative or positive. Risk of BF was analyzed using stratified cumulative incidences and multiple cause-specific Cox regression using competing risk assessment. Median follow-up was 10 years (95% CI: 9.5⁻10.2). In total, 246 patients (41.6%) had low and 346 patients (58.4%) had high 5hmC level. No significant association was found between 5hmC level or ERG expression and time to BF (p = 0.2 and p = 1.0, respectively). However, for men with ERG negative tumors, high 5hmC level was associated with increased risk of BF following RP (p = 0.01). In multiple cause-specific Cox regression analyses of ERG negative patients, high 5hmC expression was associated with time to BF (HR: 1.8; 95% CI: 1.2⁻2.7; p = 0.003). In conclusion, high 5hmC level was correlated with time to BF in men with ERG negative PCa, which is in accordance with previous results.


Assuntos
5-Metilcitosina/análogos & derivados , Prostatectomia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , 5-Metilcitosina/metabolismo , Idoso , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Curva ROC , Regulador Transcricional ERG/metabolismo
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