jorge torres

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MicroRNA promoter methylation: potential biomarkers in prostate cancer

iii A realização desta tese dependeu da ajuda de várias pessoas em diferentes momentos e circunst... more iii A realização desta tese dependeu da ajuda de várias pessoas em diferentes momentos e circunstâncias pelo que expresso aqui o meu agradecimento. À minha orientadora, Professora Doutora Carmen Jerónimo, e ao meu coorientador, Professor Doutor Rui Henrique, por me terem deixado fazer parte do Grupo de Epigenética e Biologia do Cancro, por terem acreditado em mim e me terem entregue um projeto que me deu enorme gosto trazer até aqui. Agradeço a partilha de conhecimentos, críticas, todo o acompanhamento, confiança e oportunidades que me ofereceram. Ao Professor Doutor Manuel Teixeira, por ter permitido a realização desta tese no centro de Investigação do IPO-Porto, do qual é Director. Ao João Carvalho, que me ajudou em todas as etapas deste projeto. Pela boa disposição, rigor científico, exigência e experiência que partilhou comigo. Pela paciência em explicar-me tudo o que tive que aprender e pela disponibilidade em ajudar-me na execução prática deste trabalho. Ao Pedro Pinheiro, que me ensinou muito quando entrei para o grupo e com quem tive muito gosto em trabalhar. Por ter sempre um ponto de vista a partilhar ou uma opinião para enriquecer de alguma forma tudo o que fiz no grupo, incluindo esta tese. A todos os colegas do Grupo de Epigenética e Biologia do Cancro, tanto os que agora cá estão como os que conheci e entretanto seguiram os seus caminhos, um sincero obrigado pela ajuda, disponibilidade e bom ambiente de trabalho que proporcionaram. Ao meu colega de mestrado, Hildeberto Moreira, que me ajudou muito nesta etapa académica e pela motivação constante para resolver os problemas e frustrações que fazem parte de um percurso destes. À Márcia Baixia, por estar sempre comigo, por tornar tudo mais simples e mais fácil, pela disponibilidade constante e, acima de tudo, pela compreensão e paciência inesgotáveis. Por fim, à minha família: os meus pais, a minha irmã e a minha avó. Que tornaram possível todo o meu percurso até aqui, que me incentivaram a fazer sempre o melhor possível e compreenderam os meus altos e baixos. Este estudo só foi possível com o financiamento pela Fundação para a Ciência e Tecnologia (COMPETE-FEDER-FCT) -EXPL/BIM-ONC/0556/2012 e pelo Centro de Investigação do Instituto Português de Oncologia do Porto (CI-IPOP 4-2012).

format_quoteHigher miR-129-2 methylation linked to advanced pathological stage, correlating with higher Gleason grade; AUC=0.96 for miR-193b in urinary tests.format_quote

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Author response: DNA methylome combined with chromosome cluster-oriented analysis provides an early signature for cutaneous melanoma aggressiveness

Additional file 3: of Comparing diagnostic and prognostic performance of two-gene promoter methylation panels in tissue biopsies and urines of prostate cancer patients

Figure S2. Box-plots of panel #1 (miR-34b/c, miR-193b) and panel #2 (APC, RARβ2) promoter methyla... more

Additional file 2: of Comparing diagnostic and prognostic performance of two-gene promoter methylation panels in tissue biopsies and urines of prostate cancer patients

Figure S1. Box-plots of panel #1 (miR-34b/c, miR-193b) and panel #2 (APC, GSTP1, and RARβ2) promo... more

Comparing diagnostic and prognostic performance of two-gene promoter methylation panels in tissue biopsies and urines of prostate cancer patients

Clinical epigenetics, Jan 29, 2018

Prostate cancer (PCa) is one of the most common cancers among men worldwide. Current screening me... more Prostate cancer (PCa) is one of the most common cancers among men worldwide. Current screening methods for PCa display limited sensitivity and specificity, not stratifying for disease aggressiveness. Hence, development and validation of new molecular markers is needed. Aberrant gene promoter methylation is common in PCa and has shown promise as clinical biomarker. Herein, we assessed and compared the diagnostic and prognostic performance of two-gene panel promoter methylation in the same sample sets. Promoter methylation of panel #1 (singleplex-miR-34b/c and miR-193b) and panel #2 (multiplex-APC, GSTP1, and RARβ2) was evaluated using MethyLight methodology in two different cohorts [prostate biopsy (#1) and urine sediment (#2)]. Biomarkers' diagnostic (validity estimates) and prognostic (disease-specific survival, disease-free survival, and progression-free survival) performance was assessed. Promoter methylation levels of both panels showed the highest levels in PCa samples in b...

format_quoteTwo-gene panel promoter methylation identified relapsed patients with AUC values of 0.751 and 0.765, indicating strong diagnostic potential for PCa.format_quote

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DNA methylome combined with chromosome cluster-oriented analysis provides an early signature for cutaneous melanoma aggressiveness

ABSTRACTAberrant DNA methylation is a well-known feature of tumours and has been associated with ... more ABSTRACTAberrant DNA methylation is a well-known feature of tumours and has been associated with metastatic melanoma. However, since melanoma cells are highly heterogeneous, it has been challenging to use affected genes to predict tumour aggressiveness, metastatic evolution, and patients’ outcomes. We hypothesized that common aggressive hypermethylation signatures should emerge early in tumorigenesis and should be shared in aggressive cells, independent of the physiological context under which this trait arises.We compared paired melanoma cell lines with the following properties:(i)each pair comprises one aggressive counterpart and its parental cell line, and(ii)the aggressive cell lines were each obtained from different host and their environment (human, rat, and mouse), though starting from the same parent cell line. Next, we developed a multi-step genomic pipeline that combines the DNA methylome profile with a chromosome cluster-oriented analysis.A total of 229 differentially hyp...

Additional file 2: Figure S1. of MiR-193b promoter methylation accurately detects prostate cancer in urine sediments and miR-34b/c or miR-129-2 promoter methylation define subsets of clinically aggressive tumors

Distribution of miR's promoter methylation levels in prostatic, vesical and renal tissues. MN... more

Additional file 1: Table S1. of MiR-193b promoter methylation accurately detects prostate cancer in urine sediments and miR-34b/c or miR-129-2 promoter methylation define subsets of clinically aggressive tumors

Primer sequences used for reference gene and each microRNA promoter methylation analysis. (DOC 28... more

Additional file 1: of Comparing diagnostic and prognostic performance of two-gene promoter methylation panels in tissue biopsies and urines of prostate cancer patients

Table S1. Primer sequences for β-Actin, miR-34b/c, and miR-193b (panel #1). Table S2. Scorpion pr... more Table S1. Primer sequences for β-Actin, miR-34b/c, and miR-193b (panel #1). Table S2. Scorpion primer-probe and primer inner sequences for β-Actin, APC, GSTP1, and RARβ2 (panel #2). Table S3. Diagnostic performance of each DNA methylation-based biomarker in cohort #1. Table S4. Diagnostic performance of each DNA methylation-based biomarker in cohort #2. (DOCX 22 kb)

MiR-193b promoter methylation accurately detects prostate cancer in urine sediments and miR-34b/c or miR-129-2 promoter methylation define subsets of clinically aggressive tumors

Molecular cancer, Jan 31, 2017

Contemporary challenges of prostate cancer (PCa) include overdiagnosis and overtreatment, entaili... more Contemporary challenges of prostate cancer (PCa) include overdiagnosis and overtreatment, entailing the need for novel clinical tools to improve risk stratification and therapy selection. PCa diagnosis and prognostication might be perfected using epigenetic biomarkers, among which aberrant DNA methylation of microRNA promoters has not been systematically explored. Herein, we identified aberrantly methylated microRNAs promoters in PCa and assessed its diagnostic and prognostic biomarker potential. Using HumanMethylation450 BeadChip-based analysis differentially methylated CpGs in microRNA promoters were identified. Promoter methylation of six microRNAs (miR-34b/c, miR-129-2, miR-152, miR-193b, miR-663a and miR-1258) was analyzed by qMSP in three sets (180 prostatectomies, 95 urine sediments and 74 prostate biopsies). Biomarkers' diagnostic (validity estimates) and prognostic [disease-free (DFS) and disease-specific survival (DSS)] performance was assessed. Significantly higher pr...

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MicroRNA promoter methylation: a new tool for accurate detection of urothelial carcinoma

British journal of cancer, Jan 12, 2017

Urothelial carcinoma (UC) is the most common cancer affecting the urinary system, worldwide. Lack... more Urothelial carcinoma (UC) is the most common cancer affecting the urinary system, worldwide. Lack of accurate early detection tools entails delayed diagnosis, precluding more efficient and timely treatment. In a previous study, we found that miR-129-2 and miR-663a were differentially methylated in UC compared with other genitourinary tract malignancies. Here, we evaluated the diagnostic performance of those microRNAs in urine. Promoter methylation levels of miR-129-2 and miR-663a were assessed, using real-time quantitative methylation-specific PCR, in UC tissue samples (using normal urothelium as control) and, subsequently, in urine samples from UC and other genitourinary malignancies. Diagnostic and prognostic performances were evaluated by receiver operator characteristics curve and survival analyses, respectively. Promoter methylation levels of both microRNAs were significantly higher in UC tissue samples compared with normal urothelium. In urine, the assay was able to distinguis...

format_quoteMethylation analysis showed miR-129-2 and miR-663a in UC tissues achieved 94.7% sensitivity and 84% specificity, AUC=0.941 (P<0.001).format_quote

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Epigenetic disruption of miR-130a promotes prostate cancer by targeting SEC23B and DEPDC1

Cancer Letters, 2017

MicroRNAs (miRNAs) are small, non-coding RNAs that mediate post-transcriptional gene silencing, f... more MicroRNAs (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.

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MicroRNA-375 plays a dual role in prostate carcinogenesis

Clinical Epigenetics, 2015

Background: Prostate cancer (PCa), a highly incident and heterogeneous malignancy, mostly affects... more Background: Prostate cancer (PCa), a highly incident and heterogeneous malignancy, mostly affects men from developed countries. Increased knowledge of the biological mechanisms underlying PCa onset and progression are critical for improved clinical management. MicroRNAs (miRNAs) deregulation is common in human cancers, and understanding how it impacts in PCa is of major importance. MiRNAs are mostly downregulated in cancer, although some are overexpressed, playing a critical role in tumor initiation and progression. We aimed to identify miRNAs overexpressed in PCa and subsequently determine its impact in tumorigenesis. Results: MicroRNA expression profiling in primary PCa and morphological normal prostate (MNPT) tissues identified 17 miRNAs significantly overexpressed in PCa. Expression of three miRNAs, not previously associated with PCa, was subsequently assessed in large independent sets of primary tumors, in which miR-182 and miR-375 were validated, but not miR-32. Significantly higher expression levels of miR-375 were depicted in patients with higher Gleason score and more advanced pathological stage, as well as with regional lymph nodes metastases. Forced expression of miR-375 in PC-3 cells, which display the lowest miR-375 levels among PCa cell lines, increased apoptosis and reduced invasion ability and cell viability. Intriguingly, in 22Rv1 cells, which displayed the highest miR-375 expression, knockdown experiments also attenuated the malignant phenotype. Gene ontology analysis implicated miR-375 in several key pathways deregulated in PCa, including cell cycle and cell differentiation. Moreover, CCND2 was identified as putative miR-375 target in PCa, confirmed by luciferase assay. Conclusions: A dual role for miR-375 in prostate cancer progression is suggested, highlighting the importance of cellular context on microRNA targeting.

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Anti-neoplastic properties of hydralazine in prostate cancer

Oncotarget, Jan 15, 2014

Prostate cancer (PCa) is a major cause of cancer-related morbidity and mortality worldwide. Altho... more Prostate cancer (PCa) is a major cause of cancer-related morbidity and mortality worldwide. Although early disease is often efficiently managed therapeutically, available options for advanced disease are mostly ineffective. Aberrant DNA methylation associated with gene-silencing of cancer-related genes is a common feature of PCa. Therefore, DNA methylation inhibitors might constitute an attractive alternative therapy. Herein, we evaluated the anti-cancer properties of hydralazine, a non-nucleoside DNA methyltransferases (DNMT) inhibitor, in PCa cell lines. In vitro assays showed that hydralazine exposure led to a significant dose and time dependent growth inhibition, increased apoptotic rate and decreased invasiveness. Furthermore, it also induced cell cycle arrest and DNA damage. These phenotypic effects were particularly prominent in DU145 cells. Following hydralazine exposure, decreased levels of DNMT1, DNMT3a and DNMT3b mRNA and DNMT1 protein were depicted. Moreover, a significa...

format_quoteHydralazine reversed PCa cell phenotype, decreased DNMT expression, and restored silenced genes, affecting EGF signaling pathways and cell cycle regulation.format_quote

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385: The role of miR-375 in prostate carcinogenesis

European Journal of Cancer, 2014

DISCUSSION 53 CONCLUSIONS AND FUTURE PERSPECTIVES 58 TRUS Transrectal ultrasound UICC Union for C... more

format_quoteOver 70% of men in their 80s have malignant prostate disorders, emphasizing the critical health impact of prostate disease in aging populations.format_quote

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