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1.
Sci Rep ; 11(1): 17473, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471195

RESUMO

As for all newly-emergent pathogens, SARS-CoV-2 presents with a relative paucity of clinical information and experimental models, a situation hampering both the development of new effective treatments and the prediction of future outbreaks. Here, we find that a simple virus-free model, based on publicly available transcriptional data from human cell lines, is surprisingly able to recapitulate several features of the clinically relevant infections. By segregating cell lines (n = 1305) from the CCLE project on the base of their sole angiotensin-converting enzyme 2 (ACE2) mRNA content, we found that overexpressing cells present with molecular features resembling those of at-risk patients, including senescence, impairment of antibody production, epigenetic regulation, DNA repair and apoptosis, neutralization of the interferon response, proneness to an overemphasized innate immune activity, hyperinflammation by IL-1, diabetes, hypercoagulation and hypogonadism. Likewise, several pathways were found to display a differential expression between sexes, with males being in the least advantageous position, thus suggesting that the model could reproduce even the sex-related disparities observed in the clinical outcome of patients with COVID-19. Overall, besides validating a new disease model, our data suggest that, in patients with severe COVID-19, a baseline ground could be already present and, as a consequence, the viral infection might simply exacerbate a variety of latent (or inherent) pre-existing conditions, representing therefore a tipping point at which they become clinically significant.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , Perfilação da Expressão Gênica/métodos , Regulação para Cima , COVID-19/imunologia , Linhagem Celular , Bases de Dados Genéticas , Feminino , Humanos , Imunidade Inata , Masculino , Modelos Biológicos , Modelos Teóricos , Caracteres Sexuais
2.
Transl Oncol ; 14(11): 101211, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34455373

RESUMO

AIM: Since its discovery Prostate Specific Antigen (PSA), also referred to as kallikrein-3 (KLK3), has been used as standard circulating biomarker for prostate cancer (PCa). However, its specificity remains not adequate and its mechanism of action still elusive. Therefore, deciphering PSA role throughout PCa-pathobiology would be relevant in improving both cancer diagnosis and outcome prediction. We investigated the possible role played by PSA on/in the tumor microenvironment and over the first steps of cancer invasion. METHODS: Fresh PCa-specimens and cell lines were used for ex-vivo/in-vitro invasion assays and assessment of prostate tissue-PSA (tPSA), type 1 collagen (COL1A1) and ß1-integrin expression. Tissue Cancer Genome Atlas (TCGA) and Decipher® datasets were considered to estimate tPSA clinical relevance. RESULTS: A more precise, inverse, correspondence between tPSA and clinical/pathological parameters was found than for circulating PSA. KLK3 combined with Gleason grade and pathologic stage, better predicted cancer-related mortality. Consistently, we demonstrated that PSA inhibits prostate extracellular-matrix (ECM) invasion by PCa cells. As for the mechanism of action, we provided novel information that PSA is able to cleave COL1A1, a main component of the ECM. Finally, ß1-integrin, a crucial COL1A1 transducing-receptor involved in tumor adhesion/invasion, resulted to be downregulated in PCa specimens with higher levels of tPSA. CONCLUSIONS: By interfering with type 1 collagen and its downstream targets, PSA may hamper adhesion and path of the cancer cells through ECM and their migration ability, thus explaining the inverse correlation highlighted between prostate tPSA levels and clinically significant disease.

3.
Transl Androl Urol ; 10(3): 1110-1120, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33850746

RESUMO

Background: Therapies available for late stage prostate cancer (PCa) patients are limited and mostly palliative. The necessary development of unexplored therapeutic options relies on a deeper knowledge of molecular mechanisms leading to cancer progression. Redox signals are known to modulate the intensity and duration of oncogenic circuits; cues originating from the endoplasmic reticulum (ER) and downstream exocytic organelles are relevant in secretory tumors, including PCa. Ero 1α is a master regulator of redox homeostasis and oxidative folding. Methods: We assessed Ero 1α mRNA expression by bioinformatic analysis of three public datasets and protein expression levels in PCa cell lines representing different degrees of tumor progression and different human prostate specimens. Transient Ero 1α knockdown was achieved by RNA interference (siRNA). Consequences of Ero 1α downregulation were monitored by PCa proliferation, migration and invasion properties. Results: Ero 1α mRNA and protein levels are upregulated in PCa cell lines compared to non-tumorigenic cells (P=0.0273). Ero 1α expression increases with the grade of malignancy, reaching the highest level in the androgen resistant PC3. In patients' samples from 3 datasets, Ero 1α mRNA expression correlates with pathological Gleason scores. Ero 1α knockdown inhibits proliferation (P=0.0081), migration (P=0.0085) and invasion (P=0.0007) of PC3 cells and alters the levels of integrin ß1 (P=0.0024). Conclusions: Results indicate that Ero 1α levels correlate with PCa aggressiveness; Ero 1α silencing inhibits key steps over the PCa metastatic process. Therefore, Ero 1α has the potential to be exploited as a novel biomarker and a therapeutic target in PCa.

5.
Cancers (Basel) ; 12(4)2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32260109

RESUMO

Due to the involvement of the endocannabinoid system (ECS) in cancer onset and progression and the less studied connection between ECS and bladder cancer, here an evaluation of the ECS modifications associated with bladder cancer is reported. Urine samples were collected from healthy volunteers and patients with bladder cancer at different grades. Endocannabinoids (ECs) and N-acylethanolamides (NAEs) were quantified by HPLC-MS/MS and results normalized for creatinine content. An increase in the urine concentrations of four ECs and NAEs analyzed was observed with a statistically significant increase in the arachidonoylethanolamide (AEA) and stearoylethanoamide (SEA) associated with bladder cancer. Receiver operating characteristic curves built with AEA and SEA data allowed the selection of 160 pg/mL for SEA (area under the curve (AUC) = 0.91, Selectivity (SE) 94%, Specificity (SP) 45%) and 8 pg/mL for AEA (AUC = 0.85, SE 94%, SP 61%) as the best cut-off values. Moreover, data from bladder cancer samples at different grades were derived from The Cancer Genome Atlas, and the expressions of thirteen different components of the "endocannabinoidome" were analyzed. Statistical analysis highlights significant variations in the expression of three enzymes involved in EC and NAE turnover in bladder cancer.

11.
Eur Urol ; 72(4): 625-631, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28434677

RESUMO

BACKGROUND: The advent of molecular-based methods of identification and characterization of complex microbial populations has led to a new era of microbial discovery. A detailed and comprehensive analysis of the microbial ecosystem of the pathologic and healthy prostate tissues has not been yet reported. OBJECTIVES: To characterize the microbiome possibly associated to the pathologic prostate microenvironment. DESIGN, SETTING, AND PARTICIPANTS: The microbiome profile of tumor, peri-tumor, and nontumor tissues was assessed on 16 radical prostatectomy-specimens. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Microbiome analysis was assessed by massive ultradeep pyrosequencing. Bacteria load was expressed as a percentage of the total number of bacteria. The statistical significance of differences among specimen-groups was tested with Friedman's test (Dunn posthoc test) and Wilcoxon rank-sum test. RESULTS AND LIMITATIONS: Three phyla, six classes, nine orders, 14 families, and 11 genera were above the set threshold value of 1%, respectively. Significant differences in specific microbial populations among tumor/peri-tumor and nontumor prostate specimens were observed at certain taxonomic levels. Among genera, Propionibacterium spp. were the most abundant. Staphylococcus spp. were more represented in the tumor/peri-tumor tissues (p<0.05). The restricted number of specimens represents a potential limitation. CONCLUSIONS: The prostate contains a plethora of bacteria, which set themselves within the gland with a distribution dependent on the nature of the tissue, thus suggesting a possible pathophysiological correlation between the composition of the local microbial niche and the presence of the tumor itself. Future studies will help to clarify the role of these specific bacteria and their potential to be exploited as new biomarkers. PATIENT SUMMARY: The pathological prostate is populated by specific microbial populations, whose distribution varies according to the nature of the tissue. This finding opens interesting perspectives for the identification of novel therapeutic approaches and biomarkers.


Assuntos
Bactérias/isolamento & purificação , Microbiota , Microambiente Tumoral , Bactérias/classificação , Bactérias/genética , Carga Bacteriana , Técnicas de Tipagem Bacteriana/métodos , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Filogenia , Prostatectomia , Neoplasias da Próstata/microbiologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia
12.
Sci Rep ; 7: 42157, 2017 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-28191815

RESUMO

The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may also play critical roles in controlling bladder cancer (BC). CB expression on human normal and BC specimens was tested by immunohistochemistry. Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. Cellular sphingolipids (SL) constitution and metabolism were evaluated after metabolic labelling. CB1-2 were detected in BC specimens, but only CB2 was more expressed in the tumour. Both cell lines expressed similar CB2. Exposure to CB2 agonists inhibited BC growth, down-modulated Akt, induced caspase 3-activation and modified SL metabolism. Baseline SL analysis in cell lines showed differences linked to unique migratory behaviours and cytoskeletal re-arrangements. CB2 activation changed the SL composition of more aggressive RT112 cells by reducing (p < 0.01) Gb3 ganglioside (-50 ± 3%) and sphingosine 1-phosphate (S1P, -40 ± 4%), which ended up to reduction in cell motility (-46 ± 5%) with inhibition of p-SRC. CB2-selective antagonists, gene silencing and an inhibitor of SL biosynthesis partially prevented CB2 agonist-induced effects on cell viability and motility. CB2 activation led to ceramide-mediated BC cell apoptosis independently of SL constitutive composition, which instead was modulated by CB2 agonists to reduce cell motility.


Assuntos
Carcinoma de Células de Transição/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/genética , Esfingolipídeos/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Apoptose/efeitos dos fármacos , Bioensaio , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Imuno-Histoquímica , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Transdução de Sinais , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Cicatrização/efeitos dos fármacos , Quinases da Família src/genética , Quinases da Família src/metabolismo
13.
J Clin Invest ; 126(7): 2452-64, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27214556

RESUMO

The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene-encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1-deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome P450 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insights into the molecular determinants of human congenital asplenia.


Assuntos
Proteínas de Homeodomínio/fisiologia , Transdução de Sinais , Baço/crescimento & desenvolvimento , Tretinoína/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula , Feminino , Deleção de Genes , Heterozigoto , Homozigoto , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação
14.
Pharmacol Res ; 110: 131-138, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27210721

RESUMO

Thanks to impressive technology advancements, pervasive expression of non-coding RNAs (ncRNAs) has been recently identified in the genome of numerous cancers. Long ncRNAs (lncRNAs) belong to a new class of ncRNAs including tens of thousands different species. A fraction of these molecules shows a striking cancer-enriched expression pattern, suggesting an essential role in tumor cells and, possibly, a utility in therapeutic terms. This review aims at summarizing current knowledge for the identification and validation of lncRNAs as therapeutics targets in tumors. Both in-silico and wet-biology resources are presented in relation to the many challenges that the scientific community still needs to address in terms of lncRNA identification, stratification, patient personalization, drug delivery and toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Edição de Genes/métodos , Neoplasias/terapia , RNA Longo não Codificante/efeitos dos fármacos , Terapêutica com RNAi/métodos , Animais , Sistemas CRISPR-Cas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
16.
Genom Data ; 3: 4-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26484139

RESUMO

We recently identified the long non-coding RNA (ncRNA) TRPM2-AS as a key regulator of survival in prostate cancer [1]. This essential role, coupled to the TRPM2-AS low-expression levels in healthy tissues, makes this ncRNA a suitable therapeutic target for further clinical studies. To get insights into the survival mechanism controlled by this molecule, we ablated its expression in prostate cancer cells and performed a genome-wide analysis of the transcripts differentially regulated in dying cells. Here, we describe in detail the experimental system, methods and quality control for the generation of the microarray data associated with our recent publication [1]. The data are related to [1]. Data have been deposited to the Gene Expression Omnibus (GEO) database repository with the dataset identifier GSE40687.

17.
Mult Scler ; 18(10): 1384-94, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22457343

RESUMO

BACKGROUND: The role played by genetic factors in influencing the clinical course of multiple sclerosis (MS) is not yet well established. OBJECTIVE: We aimed to identify genetic variants associated with progressive MS (PrMS). METHODS: We conducted a genome-wide association study (GWAS) in 197 patients with PrMS and 234 controls of Italian origin. We tested the top 20 single nucleotide polymorphisms (SNPs) with suggestive evidence of association (p-value<10(-4)) in two independent sets of primary progressive MS cases and controls. RESULTS: We identified a risk-associated SNP in the HLA region in linkage disequilibrium (LD) with DRB1*1501 and DQB*0602 loci, with genome-wide significance (rs3129934(T), p (combined)=6.7×10(-16), OR=2.34, 95% CI=1.90-2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343(G), p (combined)=2.4×10(-5), OR=0.70, 95% CI=0.59-0.83) which maps within a human endogenous retroviral (HERV) element. The new locus did not have a 'cis' effect on RNA expression in lymphoblastic cell lines, but pathway analyses of 'trans' effects point to an expression regulation of genes involved in neurodegeneration, including glutamate metabolism (p<0.01) and axonal guidance signalling (p<0.02). CONCLUSIONS: We have confirmed the established association with the HLA region and, despite the low statistical power of the study, we found suggestive evidence for association with a novel locus on chromosome 7, with a putative regulatory role.


Assuntos
Cromossomos Humanos Par 7/genética , Predisposição Genética para Doença/genética , Antígenos HLA/genética , Esclerose Múltipla Crônica Progressiva/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
18.
Int J Oncol ; 34(4): 1099-108, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19287968

RESUMO

Antisense transcription has long been recognized as a mechanism involved in the regulation of gene expression. Therefore, several human diseases associated with abnormal patterns of gene expression might display antisense RNA-mediated pathogenetic mechanisms. Such issue could be particularly relevant for cancer pathogenesis, since deregulated gene expression has long been established as a hallmark of cancer cells. Herein, we report on a bioinformatic search for antisense transcription in two cancer-associated regions of human chromosome 6 (6q21 and 6q27). Natural antisense transcripts (NATs) for several genes in both genomic regions were predicted in silico and subsequently validated by strand-specific RT-PCR. Detailed experimental validation by quantitative real-time RT-PCR of five putative cancer related sense-antisense transcript pairs revealed a single candidate tumor suppressor gene (RPS6KA2) whose expression levels display marked cancer-related changes that are likely mediated by its antisense RNA in a breast cancer cell line model.


Assuntos
Cromossomos Humanos Par 6 , Neoplasias/genética , RNA Antissenso/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Biologia Computacional/métodos , Genes Supressores de Tumor , Genoma Humano , Humanos , Íntrons , Modelos Biológicos , Modelos Genéticos , Neoplasias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Oligonucleotídeos Antissenso , RNA Antissenso/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Quinases S6 Ribossômicas 90-kDa/biossíntese
19.
Cell Res ; 18(11): 1128-40, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18957938

RESUMO

It has been proposed that in cancer, where the bulk of the genome becomes hypomethylated, there is an increase in transcriptional noise that might lead to the generation of antisense transcripts that could affect the function of key oncosuppressor genes, ultimately leading to malignant transformation. Here, we describe the computational identification of a melanoma-enriched antisense transcript, TRPM2-AS, mapped within the locus of TRPM2, an ion channel capable of mediating susceptibility to cell death. Analysis of the TRPM2-AS genomic region indicated the presence in the same region of another tumor-enriched TRPM2 transcript, TRPM2-TE, located across a CpG island shared with TRPM2-AS. Quantitative PCR experiments confirmed that TRPM2-AS and TRPM2-TE transcripts were up-regulated in melanoma, and their activation was consistent with the methylation status of the shared CpG island. Functional knock-out of TRPM2-TE, as well as over-expression of wild-type TRPM2, increased melanoma susceptibility to apoptosis and necrosis. Finally, expression analysis in other cancer types indicated that TRPM2-AS and TRPM2-TE over-expression might have an even wider role than anticipated, reinforcing the relevance of our computational approach in identifying new potential therapeutic targets.


Assuntos
Elementos Antissenso (Genética) , Melanoma/genética , Neoplasias Cutâneas/genética , Canais de Cátion TRPM/genética , Apoptose/genética , Caspases/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Biologia Computacional/métodos , Ilhas de CpG , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Transcrição Genética
20.
RNA ; 13(2): 223-39, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17185360

RESUMO

The ratio of noncoding to protein coding DNA rises with the complexity of the organism, culminating in nearly 99% of nonprotein coding DNA in humans. Nevertheless, a large portion of these regions is transcribed, creating the alleged paradox that noncoding RNA (ncRNA) represents the largest output of the human genome. Such a complex scenario may include epigenetic mechanisms where ncRNAs would be involved in chromatin regulation. We have investigated the intergenic, noncoding transcriptomes of mammalian HOX clusters. We show that "opposite strand transcription" from the intergenic spacer regions in the human HOXA cluster correlates with the activity state of adjacent HOXA genes. This noncoding transcription is regulated by the retinoic acid morphogen and follows the colinear activation pattern of the cluster. Opening of the cluster at sites of activation of intergenic transcripts is accompanied by changes in histone modifications and a loss of interaction with Polycomb group (PcG) repressive complexes. We propose that noncoding transcription is of fundamental importance for the opening and maintenance of the active state of HOX clusters.


Assuntos
Epigênese Genética , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , RNA não Traduzido/biossíntese , Proteínas Repressoras/metabolismo , Animais , Linhagem Celular Tumoral , Biologia Computacional , Ilhas de CpG , DNA Intergênico , Etiquetas de Sequências Expressas , Feto/química , Genes Homeobox , Histonas/metabolismo , Humanos , Metilação/efeitos dos fármacos , Camundongos , Família Multigênica , Proteínas do Grupo Polycomb , RNA/metabolismo , RNA Antissenso/genética , RNA Antissenso/metabolismo , RNA não Traduzido/genética , Elementos de Resposta , Software , Transcrição Genética , Tretinoína/farmacologia
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