Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 69
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Carcinogenesis ; 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31284295

RESUMO

Racial/ethnic disparities have a significant impact on bladder cancer outcomes with African-American patients demonstrating inferior survival over European-American patients. We hypothesized that epigenetic difference in methylation of tumor DNA is an underlying cause of this survival health disparity. We analyzed bladder tumors from African-American and European-American patients using reduced representation bisulfite sequencing (RRBS) to annotate differentially methylated DNA regions. Liquid chromatography-mass spectrometry (LC-MS/MS) based metabolomics and flux studies were performed to examine metabolic pathways that showed significant association to the discovered DNA methylation patterns. RRBS analysis showed frequent hypermethylated CpG islands in African-American patients. Further analysis showed that these hypermethylated CpG islands patients are commonly located in the promoter regions of xenobiotic enzymes that are involved in suppressing bladder cancer progression. On follow up, LC-MS/MS revealed accumulation of glucuronic acid, S-adenosylhomocysteine and a decrease in S-adenosylmethionine, corroborating findings from the RRBS and mRNA expression analysis indicating increased glucuronidation and methylation capacities in African-American patients. Flux analysis experiments with 13C labelled glucose in cultured African-American bladder cancer cells confirmed these findings. Collectively, our studies revealed robust differences in methylation-related metabolism and expression of enzymes regulating xenobiotic metabolism in African American patients indicates that race/ethnic differences in tumor biology may exist in bladder cancer.

2.
Nat Commun ; 10(1): 2148, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089135

RESUMO

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , MAP Quinase Quinase 7/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/genética , Proteínas Serina-Treonina Quinases/genética , Taxa de Sobrevida , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
3.
Cell Stem Cell ; 24(5): 753-768.e6, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982770

RESUMO

Cell-autonomous Wnt signaling has well-characterized functions in controlling stem cell activity, including in the prostate. While niche cells secrete Wnt ligands, the effects of Wnt signaling in niche cells per se are less understood. Here, we show that stromal cells in the proximal prostatic duct near the urethra, a mouse prostate stem cell niche, not only produce multiple Wnt ligands but also exhibit strong Wnt/ß-catenin activity. The non-canonical Wnt ligand Wnt5a, secreted by proximal stromal cells, directly inhibits proliefration of prostate epithelial stem or progenitor cells whereas stromal cell-autonomous canonical Wnt/ß-catenin signaling indirectly suppresses prostate stem or progenitor activity via the transforming growth factor ß (TGFß) pathway. Collectively, these pathways restrain the proliferative potential of epithelial cells in the proximal prostatic ducts. Human prostate likewise exhibits spatially restricted distribution of stromal Wnt/ß-catenin activity, suggesting a conserved mechanism for tissue patterning. Thus, this study shows how distinct stromal signaling mechanisms within the prostate cooperate to regulate tissue homeostasis.

4.
J Clin Invest ; 129(6): 2351-2356, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30920960

RESUMO

BACKGROUND: African American (AA) patients have higher cancer mortality rates and shorter survival times compared to European American (EA) patients. Despite a significant focus on socioeconomic factors, recent findings strongly argue the existence of biological factors driving this disparity. Most of these factors have been described in a cancer-type specific context rather than a pan-cancer setting. METHODS: A novel in silico approach based on Gene Set Enrichment Analysis (GSEA) coupled to Transcription Factor enrichment was carried out to identify common biological drivers of pan-cancer racial disparity using The Cancer Genome Atlas (TCGA) dataset. Mitochondrial content in patient tissues was examined using a multi-cancer tissue microarray approach (TMA). RESULTS: Mitochondrial oxidative phosphorylation was uniquely enriched in AA tumors compared to EA tumors across various cancer types. AA tumors also showed strong enrichment for the ERR1-PGC1α-mediated transcriptional program, which has been implicated in mitochondrial biogenesis. TMA analysis revealed that AA cancers harbor significantly more mitochondria compared to their EA counterparts. CONCLUSIONS: These findings highlight changes in mitochondria as a common distinguishing feature between AA and EA tumors in a pan-cancer setting, and provide the rationale for the repurposing of mitochondrial inhibitors to treat AA cancers.

5.
Chem Biol Interact ; 291: 87-94, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29913120

RESUMO

Irinotecan is highly effective in the treatment of metastatic colorectal cancer as well as many other cancers. However, irinotecan is known to cause severe diarrhea, which pose significant problems in patients undergoing irinotecan based chemotherapy. Dietary and herbal components have shown promise in improving gastrointestinal health. Therefore, we compared the effect of grain-based chow diet containing phytoestrogens and corn/alfalfa as fat source to purified diets containing either animal-derived fat source (lard) or plant-derived fat source (soybean oil) on irinotecan-induced toxicities in mice. The concentration of the toxic metabolite, SN-38, was measured in the serum, and the activity of main enzyme, carboxylesterase (CEs) involved in biotransformation of irinotecan to SN-38 formation was measured in the liver. We found that the grain-based diet was protective against irinotecan-induced diarrhea. Interestingly, purified diet containing lard caused fatty liver in mice, while grain-based chow diet containing corn/alfa-alfa or purified diet with soybean oil did not cause fat deposition in the liver. Serum SN-38 concentration was significantly higher in the mice fed with purified diets compared to the chow-fed mice. Hepatic CEs activity was induced in the presence of irinotecan in mice on purified diets, but not chow diet. These results indicate that components of grain-based natural diet (presumably phytoestrogens and/or the macronutrients balance) compared to purified diets may have a beneficial effect by controlling the adverse effects of irinotecan in cancer patients.


Assuntos
Camptotecina/análogos & derivados , Dieta , Testes de Toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Camptotecina/efeitos adversos , Camptotecina/sangue , Camptotecina/toxicidade , Carboxilesterase/metabolismo , Diarreia/sangue , Diarreia/induzido quimicamente , Fígado Gorduroso/sangue , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Glucuronidase/metabolismo , Irinotecano , Masculino , Metaboloma , Camundongos Endogâmicos C57BL
6.
J Clin Invest ; 128(7): 3129-3143, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29715200

RESUMO

Receptor tyrosine kinases (RTKs) are important drivers of cancers. In addition to genomic alterations, aberrant activation of WT RTKs plays an important role in driving cancer progression. However, the mechanisms underlying how RTKs drive prostate cancer remain incompletely characterized. Here we show that non-proteolytic ubiquitination of RTK regulates its kinase activity and contributes to RTK-mediated prostate cancer metastasis. TRAF4, an E3 ubiquitin ligase, is highly expressed in metastatic prostate cancer. We demonstrated here that it is a key player in regulating RTK-mediated prostate cancer metastasis. We further identified TrkA, a neurotrophin RTK, as a TRAF4-targeted ubiquitination substrate that promotes cancer cell invasion and found that inhibition of TrkA activity abolished TRAF4-dependent cell invasion. TRAF4 promoted K27- and K29-linked ubiquitination at the TrkA kinase domain and increased its kinase activity. Mutation of TRAF4-targeted ubiquitination sites abolished TrkA tyrosine autophosphorylation and its interaction with downstream proteins. TRAF4 knockdown also suppressed nerve growth factor (NGF) stimulated TrkA downstream p38 MAPK activation and invasion-associated gene expression. Furthermore, elevated TRAF4 levels significantly correlated with increased NGF-stimulated invasion-associated gene expression in prostate cancer patients, indicating that this signaling axis is significantly activated during oncogenesis. Our results revealed a posttranslational modification mechanism contributing to aberrant non-mutated RTK activation in cancer cells.

7.
Int J Mol Epidemiol Genet ; 8(2): 8-18, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28533893

RESUMO

Toll-like receptors (TLRs) and the receptor for advanced glycation end products (AGER) are pattern recognition receptors that regulate intestinal inflammatory homeostasis. However, their relevance in colorectal cancer (CRC) prognosis is unclear. We investigated expression of TLRs, AGER, and interacting proteins in association with CRC mortality in a retrospective cohort study of 65 males diagnosed with primary resectable CRC between 2002 and 2009. Multiplex quantitative nuclease protection assay was used to quantify the expression of 19 genes in archived tissues of tumor and paired adjacent normal mucosa. We evaluated the association between log2 (tumor/normal) expression ratios for single and combined genes and all-cause mortality using multivariable Cox regression analysis. The false discovery rate adjusted q-value less than 0.10 indicated statistical significance for single gene. Five-year survival time was calculated from diagnosis of CRC to death, lost to follow-up, or December 31, 2014. Compared to paired normal mucosa, expression levels of AGER, IL1A, MYD88, and TLR5 were lower (q = 0.0002); while CXCL8 and S100P were higher (q = 0.0002) in tumor epithelia. Higher tumor expression of IL1A (HRadj = 0.68, 95% CI: 0.49-0.94), IL6 (HRadj = 0.70, 95% CI: 0.52-0.94), MyD88 (HRadj = 0.53, 95% CI: 0.30-0.93), and TLR5 (HRadj = 0.71, 95% CI: 0.52-0.98) was associated with higher mortality risk. There was a synergistic effect on lower five-year survival in lower co-expressers of IL-6 and MyD88 (P < 0.0001). Our findings suggest that a TLRs/MyD88-mediated inflammatory response may play a role in CRC prognosis. The role of pattern recognition receptor-mediated immunity in CRC mortality warrants further research.

8.
Neoplasia ; 19(5): 421-428, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28433771

RESUMO

RCAS avian viruses have been used to deliver oncogene expression and induce tumors in transgenic mice expressing the virus receptor TVA. Here we report the generation and characterization of a novel RCAS-Cre-IRES-PyMT (RCI-PyMT) virus designed to specifically knockout genes of interest in tumors generated in appropriate mutant mouse hosts. FGF receptor 1 (FGFR1) is a gene that is amplified in human breast cancer, but there have been no definitive studies on its function in mammary tumorigenesis, progression, and metastasis in vivo in spontaneous tumors in mice. We used the retroviral tumor knockout, or TuKO, strategy to delete fgfr1 in PyMT-induced mammary tumors in K19-tva/fgfr1loxP/loxP mice. The similarly injected control K19-tva mice developed mammary tumors exhibiting high metastasis to lung, making this an ideal model for breast cancer metastasis. The fgfr1 TuKO tumors showed significantly decreased primary tumor growth and, most importantly, greatly reduced metastasis to lung. In contrast to previous reports, FGFR1 action in this spontaneous mammary tumor model does not significantly induce epithelial-to-mesenchymal transition. Loss of FGFR1 does generate a gene signature that is reverse correlated with FGFR1 gene amplification and/or upregulation in human breast cancer. Our results suggest that FGFR1 signaling is a key pathway driving breast cancer lung metastasis and that targeting FGFR1 in breast cancer is an exciting approach to inhibit metastasis.


Assuntos
Neoplasias da Mama/genética , Neoplasias Mamárias Animais/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Retroviridae/genética , Animais , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Transferência de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Animais/terapia , Camundongos , Metástase Neoplásica , Deleção de Sequência/genética
9.
Nat Commun ; 7: 13362, 2016 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-27869122

RESUMO

The importance of translational regulation in tumour biology is increasingly appreciated. Here, we leverage polyribosomal profiling to prospectively define translational regulatory programs underlying epithelial-to-mesenchymal transition (EMT) in breast epithelial cells. We identify a group of ten translationally regulated drivers of EMT sharing a common GU-rich cis-element within the 3'-untranslated region (3'-UTR) of their mRNA. These cis-elements, necessary for the regulatory activity imparted by these 3'-UTRs, are directly bound by the CELF1 protein, which itself is regulated post-translationally during the EMT program. CELF1 is necessary and sufficient for both mesenchymal transition and metastatic colonization, and CELF1 protein, but not mRNA, is significantly overexpressed in human breast cancer tissues. Our data present an 11-component genetic pathway, invisible to transcriptional profiling approaches, in which the CELF1 protein functions as a central node controlling translational activation of genes driving EMT and ultimately tumour progression.


Assuntos
Proteínas CELF1/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Regulação da Expressão Gênica/fisiologia , Animais , Neoplasias da Mama , Proteínas CELF1/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Células Epiteliais , Feminino , Redes Reguladoras de Genes , Humanos , Camundongos , Neoplasias Experimentais , Estudos Prospectivos , Análise Serial de Proteínas , Biossíntese de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Mol Cell ; 63(6): 976-89, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27594448

RESUMO

Prostate inflammation has been suggested as an etiology for benign prostatic hyperplasia (BPH). We show that decreased expression of the androgen receptor (AR) in luminal cells of human BPH specimens correlates with a higher degree of regional prostatic inflammation. However, the cause-and-effect relationship between the two events remains unclear. We investigated specifically whether attenuating AR activity in prostate luminal cells induces inflammation. Disrupting luminal cell AR signaling in mouse models promotes cytokine production cell-autonomously, impairs epithelial barrier function, and induces immune cell infiltration, which further augments local production of cytokines and chemokines including Il-1 and Ccl2. This inflammatory microenvironment promotes AR-independent prostatic epithelial proliferation, which can be abolished by ablating IL-1 signaling or depleting its major cellular source, the macrophages. This study demonstrates that disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for prostate-related diseases.


Assuntos
Células Epiteliais/metabolismo , Homeostase/genética , Macrófagos/metabolismo , Próstata/metabolismo , Hiperplasia Prostática/genética , Receptores Androgênicos/genética , Animais , Proliferação de Células , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Homeostase/imunologia , Humanos , Inflamação , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Infiltração de Neutrófilos , Próstata/imunologia , Próstata/patologia , Hiperplasia Prostática/imunologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Receptores Androgênicos/imunologia , Transdução de Sinais , Células Estromais/imunologia , Células Estromais/metabolismo , Células Estromais/patologia
11.
Discoveries (Craiova) ; 4(2)2016 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27376150

RESUMO

The Replication-Competent Avian Sarcoma-leukosis virus long-terminal repeat with splice acceptor (RCAS)-Tumor Virus A (TVA) gene delivery system has been created based on the fact that avian sarcoma leukosis virus subgroup A only infects cells expressing its receptor, TVA. This system has been successfully applied to create various mouse models for human cancers. Here we briefly discuss the advantages and the potential caveats of using this RCAS-TVA gene delivery system in cancer research. We also introduce and discuss how our newly designed RCAS-based gene delivery system (RCI-Oncogene, for RCAS-Cre-IRES-Oncogene) allows concise and efficient manipulation of gene expression in tumors in vivo, and how this system can be used to rapidly study the biological function of gene(s) and/or the collaborative actions of multiple genes in regulating tumor initiation, progression and/or metastasis.

12.
Oncotarget ; 7(30): 47891-47903, 2016 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-27374105

RESUMO

GATA transcription factors are essential in mammalian cell lineage determination and have a critical role in cancer development. In cultured prostate cancer cells, GATA2 coordinates with androgen receptor (AR) to regulate gene transcription. In the murine prostate, among six GATA members, GATA2 and GATA3 are expressed. Immunofluorescence staining revealed that both GATA factors predominantly localize in the nuclei of luminal epithelial cells. The pioneer factor FoxA1 is exclusively detected in the luminal cells, whereas AR is detected in both luminal and basal cells. Using genetic engineering, we generated prostate-specific GATA2 and GATA3 knockout (KO) mice. Ablation of single GATA gene had marginal effect on prostate morphology and AR target gene expression, likely due to their genetic compensation. Double KO mice exhibited PIN III to IV lesions, but decreased prostate to body weight ratio, altered AR target gene expression, and expansion of p63-positive basal cells. However, deletion of GATA2 and GATA3 did not reduce the mRNA or protein levels of AR or FoxA1, indicating that GATA factors are not required for AR or FoxA1 expression in adult prostate. Surprisingly, GATA2 and GATA3 exhibit minimal expression in the ventral prostatic (VP) lobe. In contrast, FoxA1 and AR expression levels in VP are at least as high as those in anterior prostatic (AP) and dorsal-lateral prostatic (DLP) lobes. Together, our results indicate that GATA2 and GATA3 are essential for adult murine prostate function and in vivo AR signaling, and the lack of the GATA factor expression in the VP suggests a fundamental difference between VP and other prostatic lobes.


Assuntos
Fatores de Transcrição GATA/metabolismo , Próstata/fisiologia , Receptores Androgênicos/metabolismo , Animais , Fatores de Transcrição GATA/genética , Engenharia Genética/métodos , Fator 3-alfa Nuclear de Hepatócito/biossíntese , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Próstata/metabolismo , Receptores Androgênicos/genética
13.
J Clin Invest ; 126(7): 2626-41, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27294523

RESUMO

Although Notch signaling is deregulated in prostate cancer, the role of this pathway in disease development and progression is not fully understood. Here, we analyzed 2 human prostate cancer data sets and found that higher Notch signaling correlates with increased metastatic potential and worse disease survival rates. We used the Pten-null mouse prostate cancer model to investigate the function of Notch signaling in the initiation and progression of prostate cancer. Disruption of the transcription factor RBPJ in Pten-null mice revealed that endogenous canonical Notch signaling is not required for disease initiation and progression. However, augmentation of Notch activity in this model promoted both proliferation and apoptosis of prostate epithelial cells, which collectively reduced the primary tumor burden. The increase in cellular apoptosis was linked to DNA damage-induced p53 activation. Despite a reduced primary tumor burden, Notch activation in Pten-null mice promoted epithelial-mesenchymal transition and FOXC2-dependent tumor metastases but did not confer resistance to androgen deprivation. Notch activation also resulted in transformation of seminal vesicle epithelial cells in Pten-null mice. Our study highlights a multifaceted role for Notch signaling in distinct aspects of prostate cancer biology and supports Notch as a potential therapeutic target for metastatic prostate cancer.


Assuntos
Metástase Neoplásica , PTEN Fosfo-Hidrolase/metabolismo , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Receptor Notch1/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Genótipo , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Receptores Notch/metabolismo , Transdução de Sinais
14.
Prostate ; 76(14): 1271-84, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27272765

RESUMO

BACKGROUND: TMPRSS2-ERG fusion occurs in about half of prostate cancers and results in over-expression of the oncogenic ERG protein in the prostate. The mechanism by which ERG contributes to prostate cancer initiation and progression remains largely unknown. Because ERG is a transcriptional activator, we reasoned that the target genes regulated by ERG could contribute to prostate cancer development. METHODS: In a search for ERG target genes, we took advantage of published datasets from the MSKCC Prostate Oncogene Project, in which a comprehensive analysis was applied to define transcriptomes in 150 prostate tumors. We retrieved the mRNA expression dataset, split them based on ERG expression, and identified genes whose expression levels are associated with ERG mRNA levels. RESULTS: mRNA expression levels of 21 genes were found to be significantly increased, while for one gene it was decreased in ERG-positive prostate tumors. Among them, the expression of TDRD1 was the most significantly increased in ERG-positive tumors. Among 131 primary prostate tumors which were primarily from European American patients, TDRD1 is over-expressed in 68% of samples, while ERG is overexpressed in 48% of samples, suggesting an additional ERG-independent mechanism of TDRD1 overexpression. In African American prostate tumors, TDRD1 mRNA is expressed in 44%, while ERG is expressed in 24% of samples. In normal tissues, TDRD1 mRNA is exclusively expressed in germ cells and its protein is also known as cancer/testis antigen 41.1 (CT41.1). We generated a mouse monoclonal antibody that recognizes human TDRD1 protein with high specificity and sensitivity. By Western blot analysis and immunohistochemistry (IHC) staining, we demonstrate that TDRD1 protein is expressed in the majority of human prostate tumors, but not in normal prostate tissue. Finally, TDRD1 is not induced in the prostate of ERG overexpression transgenic mice, suggesting that such model does not fully recapitulate the TMPRSS2/ERG fusion-dependent human prostate cancer development. CONCLUSIONS: Our results suggest TDRD1 as a novel prostate cancer biomarker. As an ERG target gene, TDRD1 might play an important role in human prostate cancer development, and as a cancer/testis antigen, TDRD1 might have long-term potential to be a therapeutic target for prostate cancer immunotherapy. Prostate 76:1271-1284, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Transporte/genética , Marcação de Genes/métodos , Células Germinativas , Neoplasias da Próstata/genética , Animais , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/biossíntese , Linhagem Celular Tumoral , Células Germinativas/metabolismo , Células Germinativas/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Regulador Transcricional ERG/biossíntese , Regulador Transcricional ERG/genética
15.
Oncotarget ; 7(25): 37993-38003, 2016 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-27191272

RESUMO

The TMPRSS2-ERG fusion occurs in approximately 50% of prostate cancer (PCa), resulting in expression of the oncogenic ERG in the prostate. Because ERG is a transcriptional activator, we hypothesized that ERG-regulated genes contribute to PCa development. Since microRNA (miRNA) has crucial functions in cancer, we searched for miRNAs regulated by ERG in PCas. We mined published datasets based on the MSKCC Prostate Oncogene Project, in which a comprehensive analysis defined the miRNA transcriptomes in 113 PCas. We retrieved the miRNA expression datasets, and identified miRNAs differentially expressed between ERG-positive and ERG-negative samples. Out of 369 miRNAs, miR-200a, -200b, -429 and -205 are the only miRNAs significantly increased in ERG-positive tumors. Strikingly, miR-200a, -200b and -429 are transcribed as a single polycistronic transcript, suggesting they are regulated at the transcriptional level. With ChIP-qPCR and in vitro binding assay, we identified two functional ETS motifs in the miR-200b/a/429 gene promoter. Knockdown of ERG in PCa cells reduced expression of these three miRNAs. In agreement with the well-established tumor suppressor function, overexpression of the miR-200b/a/429 gene inhibited PCa cell growth and invasion. In summary, our study reveals that miR-200b/a/429 is an ERG target gene, which implicates an important role in TMPRSS2/ERG-dependent PCa development. Although induction of the tumor suppressive miR-200b subfamily by oncogenic ERG appears to be counterintuitive, it is consistent with the observation that the vast majority of primary prostate cancers are slow-growing and indolent.


Assuntos
MicroRNAs/genética , Neoplasias da Próstata/genética , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neoplasias da Próstata/patologia , Regulador Transcricional ERG/genética , Transfecção
16.
Nat Commun ; 7: 11612, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-27194471

RESUMO

The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC.


Assuntos
Hexosaminas/biossíntese , Neoplasias de Próstata Resistentes à Castração/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Linhagem Celular , Humanos , Masculino , Camundongos , Camundongos SCID , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo
17.
Nat Commun ; 7: 11418, 2016 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-27108958

RESUMO

Although early detection and treatment of prostate cancer (PCa) improves outcomes, many patients still die of metastatic PCa. Here, we report that metastatic PCa exhibits reduced levels of the microRNAsmiR-101 and miR-27a. These micro-RNAs (miRNAs) negatively regulate cell invasion and inhibit the expression of FOXM1 and CENPF, two master regulators of metastasis in PCa. Interestingly, the repression of FOXM1 and CENPF by these miRNAs occurs through COUP-TFII, a member of the orphan nuclear receptors family. Loss of miR-101 positively correlates with the increase of COUP-TFII-FOXM1-CENPF activity in clinical PCa data sets, implicating clinical relevance of such regulation. Further studies show that COUP-TFII is a critical factor controlling metastatic gene networks to promote PCa metastasis. Most importantly, this miRNA-COUP-TFII-FOXM1-CENPF regulatory axis is also involved in the development of enzalutaminde resistance. Taken together, our findings highlight the contribution of specific miRNAs through the regulation of the COUP-TFII-FOXM1-CENPF cascade in PCa metastasis and drug resistance.


Assuntos
Fator II de Transcrição COUP/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteína Forkhead Box M1/metabolismo , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Fator II de Transcrição COUP/genética , Proteínas Cromossômicas não Histona/genética , Proteína Forkhead Box M1/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Metástase Neoplásica , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
18.
Clin Cancer Res ; 22(15): 3937-49, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-26968201

RESUMO

PURPOSE: Castration therapy in advanced prostate cancer eventually fails and leads to the development of castration-resistant prostate cancer (CRPC), which has no cure. Characteristic features of CRPC can be increased androgen receptor (AR) expression and altered transcriptional output. We investigated the expression of nuclear receptor corepressor 1 (NCOR1) in human prostate and prostate cancer and the role of NCOR1 in response to antiandrogens. EXPERIMENTAL DESIGN: NCOR1 protein levels were compared between matched normal prostate and prostate cancer in 409 patient samples. NCOR1 knockdown was used to investigate its effect on bicalutamide response in androgen-dependent prostate cancer cell lines and transcriptional changes associated with the loss of NCOR1. NCOR1 transcriptional signature was also examined in prostate cancer gene expression datasets. RESULTS: NCOR1 protein was detected in cytoplasm and nuclei of secretory epithelial cells in normal prostate. Both cytoplasmic and nuclear NCOR1 protein levels were lower in prostate cancer than in normal prostate. Prostate cancer metastases show significant decrease in NCOR1 transcriptional output. Inhibition of LNCaP cellular proliferation by bicalutamide requires NCOR1. NCOR1-regulated genes suppress cellular proliferation and mediate bicalutamide resistance. In the mouse, NCOR1 is required for bicalutamide-dependent regulation of a subset of the AR target genes. CONCLUSIONS: In summary, we demonstrated that NCOR1 function declines with prostate cancer progression. Reduction in NCOR1 levels causes bicalutamide resistance in LNCaP cells and compromises response to bicalutamide in mouse prostate in vivo Clin Cancer Res; 22(15); 3937-49. ©2016 AACR.


Assuntos
Expressão Gênica , Correpressor 1 de Receptor Nuclear/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Androgênios/metabolismo , Androgênios/farmacologia , Anilidas/farmacologia , Anilidas/uso terapêutico , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Metástase Neoplásica , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Correpressor 1 de Receptor Nuclear/metabolismo , Neoplasias da Próstata/terapia , Interferência de RNA , Compostos de Tosil/farmacologia , Compostos de Tosil/uso terapêutico , Transcriptoma
19.
Cell Rep ; 14(4): 907-919, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26804919

RESUMO

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of ß-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.


Assuntos
Adenocarcinoma/genética , Proteínas de Ligação a DNA/genética , Neoplasias Duodenais/genética , Mutação , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Via de Sinalização Wnt , Adenocarcinoma/metabolismo , Ampola Hepatopancreática/patologia , Sequência de Bases , Neoplasias Duodenais/metabolismo , Instabilidade Genômica , Humanos , Repetições de Microssatélites , Dados de Sequência Molecular , Neoplasias Pancreáticas/metabolismo
20.
PLoS One ; 10(6): e0128467, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26061636

RESUMO

Unlike cancers of related exocrine tissues such as the mammary and prostate gland, diagnosis and treatment of aggressive salivary gland malignancies have not markedly advanced in decades. Effective clinical management of malignant salivary gland cancers is undercut by our limited knowledge concerning the key molecular signals that underpin the etiopathogenesis of this rare and heterogeneous head and neck cancer. Without knowledge of the critical signals that drive salivary gland tumorigenesis, tumor vulnerabilities cannot be exploited that allow for targeted molecular therapies. This knowledge insufficiency is further exacerbated by a paucity of preclinical mouse models (as compared to other cancer fields) with which to both study salivary gland pathobiology and test novel intervention strategies. Using a mouse transgenic approach, we demonstrate that deregulation of the Receptor Activator of NFkB Ligand (RANKL)/RANK signaling axis results in rapid tumor development in all three major salivary glands. In line with its established role in other exocrine gland cancers (i.e., breast cancer), the RANKL/RANK signaling axis elicits an aggressive salivary gland tumor phenotype both at the histologic and molecular level. Despite the ability of this cytokine signaling axis to drive advanced stage disease within a short latency period, early blockade of RANKL/RANK signaling markedly attenuates the development of malignant salivary gland neoplasms. Together, our findings have uncovered a tumorigenic role for RANKL/RANK in the salivary gland and suggest that targeting this pathway may represent a novel therapeutic intervention approach in the prevention and/or treatment of this understudied head and neck cancer.


Assuntos
Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Neoplasias das Glândulas Salivares/etiologia , Animais , Carcinogênese , Proliferação de Células , Camundongos , Camundongos Transgênicos , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA