Browsing by Author "Antunes, Luís"
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- Epigenetic disruption of miR-130a promotes prostate cancer by targeting SEC23B and DEPDC1Publication . Ramalho-Carvalho, João; Martins, João Barbosa; Cekaite, Lina; Sveen, Anita; Torres-Ferreira, Jorge; Pinho dos Santos Graça, Maria Inês; Costa-Pinheiro, Pedro; Eilertsen, Ina Andrassy; Antunes, Luís; Oliveira, Jorge; Lothe, Ragnhild A.; Henrique, Rui; Jerónimo, CarmenMicroRNAs (miRNAs) are small, non-coding RNAs that mediate post-transcriptional gene silencing, fine tuning gene expression. In an initial screen, miRNAs were found to be globally down-regulated in prostate cancer (PCa) cell lines and primary tumors. Exposure of PCa cell lines to a demethylating agent, 5-Aza-CdR resulted in an increase in the expression levels of miRNAs in general. Using stringent filtering criteria miR-130a was identified as the most promising candidate and selected for validation analyses in our patient series. Down-regulation of miR-130a was associated with promoter hypermethylation. MiR-130a methylation levels discriminated PCa from non-malignant tissues (AUC=0.956), and urine samples revealed high specificity for non-invasive detection of patients with PCa (AUC=0.89). Additionally, repressive histone marks were also found in the promoter of miR-130a. Over-expression of miR-130a in PCa cells reduced cell viability and invasion capability, and increased apoptosis. Putative targets of miR-130a were assessed by microarray expression profiling and DEPD1C and SEC23B were selected for validation. Silencing of both genes resembled the effect of over-expressing miR-130a in PCa cells. Our data indicate that miR-130a is an epigenetically regulated miRNA involved in regulation of key molecular and phenotypic features of prostate carcinogenesis, acting as a tumor suppressor miRNA.
- Expression of histone methyltransferases as novel biomarkers for renal cell tumor diagnosis and prognosticationPublication . Pires-Luís, Ana Sílvia; Vieira-Coimbra, Marcia; Quintela Vieira, Ana Filipa; Costa-Pinheiro, Pedro; Silva-Santos, Rui; Dias, Paula C; Antunes, Luís; Lobo, Francisco; Oliveira, Jorge; Gonçalves, Céline S; Costa, Bruno M; Henrique, Rui; Jerónimo, CarmenRenal cell tumors (RCTs) are the most lethal of the common urological cancers. The widespread use of imaging entailed an increased detection of small renal masses, emphasizing the need for accurate distinction between benign and malignant RCTs, which is critical for adequate therapeutic management. Histone methylation has been implicated in renal tumorigenesis, but its potential clinical value as RCT biomarker remains mostly unexplored. Hence, the main goal of this study was to identify differentially expressed histone methyltransferases (HMTs) and histone demethylases (HDMs) that might prove useful for RCT diagnosis and prognostication, emphasizing the discrimination between oncocytoma (a benign tumor) and renal cell carcinoma (RCC), especially the chromophobe subtype (chRCC). We found that the expression levels of 3 genes--SMYD2, SETD3, and NO66--was significantly altered in a set of RCTs, which was further validated in a large independent cohort. Higher expression levels were found in RCTs compared to normal renal tissues (RNTs) and in chRCCs comparatively to oncocytomas. SMYD2 and SETD3 mRNA levels correlated with protein expression assessed by immunohistochemistry. SMYD2 transcript levels discriminated RCTs from RNT, with 82.1% sensitivity and 100% specificity [area under curve (AUC) = 0.959], and distinguished chRCCs from oncocytomas, with 71.0% sensitivity and 73.3% specificity (AUC = 0.784). Low expression levels of SMYD2, SETD3, and NO66 were significantly associated with shorter disease-specific and disease-free survival, especially in patients with non-organ confined tumors. We conclude that expression of selected HMTs and HDMs might constitute novel biomarkers to assist in RCT diagnosis and assessment of tumor aggressiveness.
- High immunoexpression of Ki67, EZH2, and SMYD3 in diagnostic prostate biopsies independently predicts outcome in patients with prostate cancerPublication . Lobo, João; Rodrigues, Ângelo; Antunes, Luís; Pinho dos Santos Graça, Maria Inês; Ramalho-Carvalho, João; Quintela Vieira, Ana Filipa; Martins, Ana Teresa; Oliveira, Jorge; Jerónimo, Carmen; Henrique, RuiOvertreatment is a major concern in patients with prostate cancer (PCa). Prognostic biomarkers discriminating indolent from aggressive disease in prostate biopsy are urgently needed. We aimed to evaluate the prognostic value of Ki67, EZH2, LSD1, and SMYD3 immunoexpression in diagnostic biopsies from a cohort of PCa patients with long term follow-up. A series of 189 consecutive prostate biopsies diagnosed with PCa (1997–2001) in a cancer center was included in the study, with follow-up last updated in November 2016. Biopsies were reviewed and graded according to 2016 WHO criteria. Immunohistochemistry was performed in the most representative block. Nuclear staining was assessed using digital image analysis. Study outcomes included disease-specific, disease-free, and progression-free survival. Statistical analysis was tabulated using SPSS version 22.0. Survival curves and hazard ratios (HRs) were estimated using Kaplan-Meyer and Cox-regression models, respectively. Statistical significance was set at P<0.05. The proportion of patients who completed the study was 177/189 (94%). In univariable analysis, high Ki67, EZH2, and SMYD3 immunoexpression associated with significantly worse disease-specific survival (HR = 1.86, 95% CI: 1.05–3.29; HR = 1.87, 95% CI: 1.10–3.27; HR = 2.68, 95% CI: 1.02–7.92). In multivariable analysis, the 3 biomarkers displayed significantly worse DSS adjusted for CAPRA score (HR = 1.78, 95% CI: 1.01–3.16; HR = 1.93, 95% CI: 1.12–3.32; HR = 2.71, 95% CI: 1.04–7.10). Among patients with low/intermediate risk CAPRA score, high Ki67 immunoexpression identified those more prone to experience disease recurrence (HR = 9.20, 95% CI: 1.27–66.44) and progression (HR = 2.97, 95% CI: 1.05–8.43). High Ki67, EZH2, and SMYD3 immunoexpression, adjusted for standard clinicopathological parameters, independently predicts outcome in patients with PCa, at diagnosis. This might assist in discriminating indolent from aggressive PCa, improving treatment selection.
- Phenotypic impact of deregulated expression of class I histone deacetylases in urothelial cell carcinoma of the bladderPublication . Neto, Susana; Quintela Vieira, Ana Filipa; Montezuma, Diana; Costa, Natália R.; Antunes, Luís; Baptista, Tiago; Oliveira, Ana Isabel; Pinho dos Santos Graça, Maria Inês; Rodrigues, Ângelo; Magalhães, José S.; Oliveira, Jorge; Henrique, Rui; Jerónimo, CarmenDeregulated expression of histone deacetylases (HDACs) has been implicated in tumorigenesis. Herein, we investigated class I HDACs expression in bladder urothelial cell carcinoma (BUCC), its prognostic value and biological significance. Significantly increased transcript levels of all HDACs were found in BUCC compared to 20 normal mucosas, and these were higher in lower grade and stage tumors. Increased HDAC3 levels were associated with improved patient survival. SiRNA experiments showed decrease cell viability and motility, and increased apoptosis. We concluded that class I HDACs play an important role in bladder carcinogenesis through deregulation of proliferation, migration and apoptosis, constituting putative therapeutic targets.
- Trends in Cyber-Physical Multi-Agent Systems. The PAAMS Collection - 15th International Conference, PAAMS 2017Publication . Prieta, Fernando De la; Vale, Zita; Antunes, Luís; Pinto, Tiago; Campbell, Andrew T.; Julián, Vicente; Neves, Antonio J.R.; Moreno, María N.PAAMS, the International Conference on Practical Applications of Agents and Multi-Agent Systems is an evolution of the International Workshop on Practical Applications of Agents and Multi-Agent Systems. PAAMS is an international yearly tribune to present, to discuss, and to disseminate the latest developments and the most important outcomes related to real-world applications. It provides a unique opportunity to bring multi-disciplinary experts, academics and practitioners together to exchange their experience in the development of Agents and Multi-Agent Systems. This volume presents the papers that have been accepted for the 2017 in the special sessions: Agent-Based Social Simulation, Modelling and Big-Data Analytics (ABM); Advances on Demand Response and Renewable Energy Sources in Agent Based Smart Grids (ADRESS); Agents and Mobile Devices (AM); Computer vision in Multi-Agent Robotics (RV); Persuasive Technologies (PT); Web and Social Media Mining (WASMM). The volume also includes the papers accepted for publication in the Doctoral Consortium (DCAI, DCAI-DECON, ISAMI, MIS4TEL, PAAMS, PACBB 2017 conferences).