DNA Methylation of PI3K/AKT pathway-related genes predicts outcome in patients with pancreatic cancer: a comprehensive bioinformatics-based study

Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.This work was supported by the FCT Research Center Grant UID/BIM/04773/2013 CBMR 1334, Câmara Municipal de Loulé, by the Liga Portuguesa Contra o Cancro/Portuguese League against Cancer through the Grant LPCC-PT Foundation 2016 to V.P.R. and by the Spanish Ministry of Science, Innovation and Universities through Grant RTI2018-094629-B-I00 to W.L.info:eu-repo/semantics/publishedVersio

DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study

Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets

Epigenetic Regulation of Signalling Pathways in Pancreatic Cancer

Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2017Pancreatic cancer is one of the most lethal malignancies worldwide. Deregulation of epigenetic marks is known to alter the expression of crucial genes for cancer development. Replicative immortality, achieved mainly through telomerase reactivation, and aberrant activation of the PI3K/Akt, Wnt, Notch and Hedgehog pathways triggers transduction cascades that potentiate cell proliferation. The aim of this study is to evaluate epigenetic alterations of genes related with these biological processes as potential pancreatic cancer biomarkers. Gene selection of the PI3K/Akt, Wnt, Notch and Hedgehog pathways was based on differential expression between normal and malignant tissue using the pancreatic expression database and the miRDB database was used to uncover miRNAs targeting the selected genes. Methylation and miRNA analysis was performed using The Cancer Genome Atlas (TCGA) data on the cohort of pancreatic cancer and the impact of DNA methylation and miRNA expression on patient’s outcome was also analysed. Most of the selected genes presented higher expression in tumour tissue. Our results reveal that the majority of the CpGs sites analysed were hypermethylated in tumour tissue. Methylation levels of the selected genes allowed the distinction between normal and malignant tissue even in initial stages of the disease revealing its potential as a diagnostic tool for pancreatic cancer. The methylation levels of the TERT, ITGA4, SFN, ITGA2, PIK3R1 and SFRP2 genes could act as independent prognostic indicators of patients’ survival with higher sensitivity and specificity than the currently implemented biomarker. Additionally, differential methylation of the TERT, SFN and PIK3R1 genes were also associated with recurrence of the patients. Moreover, analysis of the expression of miRNAs involved in the regulation of the TGFBR1, PTEN, EIF4EBP1, AKT3, JAG1 and CSNK1A1 have demonstrated the ability to discriminate between groups of patients with different outcomes when comparing the patients with highest and lowest expression of each miRNAs. Despite the promising results in this area no epigenetic biomarkers have reached the clinic yet. Our results reveal that the methylation levels of genes involved in pancreatic carcinogenesis could be used to predict the outcome of pancreatic cancer patients with high sensitivity and specificity. These results provide new evidences of the potential of epigenetic alterations as pancreatic cancer biomarkers for disease screening and management.O cancro do pâncreas é um dos mais letais em todo o mundo e a desregulação do padrão epigenético das células influencia a expressão de genes cruciais para o desenvolvimento e progressão da doença. A capacidade ilimitada de autorrenovação celular resultante principalmente da reativação da enzima telomerase e a ativação das vias de sinalização PI3K/Akt, Wnt, Notch e Hedgehog desencadeia cascatas de transdução de sinal que potenciam a proliferação celular contribuindo para o processo carcinogénico. O principal objetivo deste estudo é avaliar alterações epigenéticas de genes relacionados com estes processos biológicos como potenciais biomarcadores para o cancro do pâncreas. A selecção dos genes envolvidos nas vias de sinalização PI3K/Akt, Wnt, Notch e Hedgehog foi baseada na expressão diferencial dos genes entre tecido normal e maligno usando a base de dados Pancreatic Expression Database e para a selecção de miRNAs envolvidos na regulação dos genes de interesse recorremos à base de dados miRDB. Os níveis de metilação e de expressão dos miRNAs foram analisados usando os dados do The Cancer Genome Atlas (TCGA) relativos à coorte de pacientes com cancro do pâncreas e o seu potencial para discriminar entre pacientes com diferentes desfechos clínicos e para identificar os pacientes que se encontram em maior risco de progressão da doença assim como uma menor sobrevivência dos pacientes foi avaliado. A maioria dos genes selecionados apresentou maior expressão no tecido tumoral. Os nossos resultados revelam que a maioria das regiões genómicas analisadas estão hipermetiladas no tecido tumoral e que os níveis de metilação dos genes selecionados permitem a distinção entre tecido normal e maligno mesmo nos estadios iniciais da doença, revelando seu potencial como biomarcador de diagnóstico para o cancro de pâncreas. A metilação dos genes TERT, ITGA4, SFN, ITGA2, PIK3R1 e SFRP2 permitiram discriminar entre grupos de pacientes com diferentes desfechos clínicos considerando o seu tempo de sobrevida com maior sensibilidade e especificidade que o biomarcador atualmente implementado na clinica para este tipo de cancro. Adicionalmente, a metilação diferencial dos genes TERT, SFN and PIK3R1 revelou estar também associada com a recorrência dos pacientes. Além disso, a análise de expressão de miRNAs envolvidos na regulação dos genes TGFBR1, PTEN, EIF4EBP1, AKT3, JAG1 and CSNK1A1 permitiu diferenciar grupos de pacientes com diferentes tempos de sobrevivência comparando os pacientes com maior e menor expressão de cada miRNA. Os resultados obtidos demonstram o potencial da análise de metilação do DNA e dos níveis de miRNAs como indicadores de prognóstico com elevada sensibilidade e especificidade. Este estudo revela novas evidências sobre o potencial das alterações epigenéticas como biomarcadores de diagnóstico e prognóstico para o cancro do pâncreas de modo a contribuir para uma melhoria da qualidade e esperança de vida de pacientes com esta doença.Center for Biomedical Research (CBMR), Algarve Universit

Physiological resilience of a temperate soft coral to ocean warming and acidification

Atmospheric concentration of carbon dioxide (CO2) is increasing at an unprecedented rate and subsequently leading to ocean acidification. Concomitantly, ocean warming is intensifying, leading to serious and predictable biological impairments over marine biota. Reef-building corals have proven to be very vulnerable to climate change, but little is known about the resilience of non-reef-building species. In this study, we investigated the effects of ocean warming and acidification on the antioxidant enzyme activity (CAT-catalase, and GST-glutathione S-transferase), lipid peroxidation (using malondialdehyde, MDA-levels as a biomarker) and heat shock response (HSP70/HSC70 content) of the octocoral Veretillum cynomorium. After 60 days of acclimation, no mortalities were registered in all treatments. Moreover, CAT and GST activities, as well as MDA levels, did not change significantly under warming and/or acidification. Heat shock response was significantly enhanced under warming, but high CO2 did not have a significant effect. Contrasting to many of their tropical coral-reef relatives, our findings suggest that temperate shallow-living octocorals may be able to physiologically withstand future conditions of increased temperature and acidification.info:eu-repo/semantics/publishedVersio

Nudibranchs out of water: long-term temporal variations in the abundance of two Dendrodoris species under emersion

Abstract The sudden appearance and disappearance of nudibranchs in intertidal areas have puzzled researchers all over the world, giving rise to a great diversity of theories to explain it. Here we conducted a five-year survey to evaluate seasonal changes in the abundance of Dendrodoris herytra and D. grandiflora in the Sado estuary (Portugal) and to explore a possible relationship with environmental factors such as temperature, salinity, turbidity and dissolved oxygen. Moreover, we report, for the first time, the capacity of Dendrodoris nudibranchs to tolerate emersion (unhidden and completely exposed to sun exposure) during low tides. Our results showed that both species consistently started to appear emerged in March, reaching a peak abundance between April and May, and completely disappearing in July. In both species, this temporal trend was significantly associated with water temperature, turbidity, and dissolved oxygen, but not with salinity. We argue that the sudden appearance and disappearance of these nudibranchs in intertidal areas may result from a seasonal horizontal movement of adult nudibranchs from subtidal areas to mate in intertidal areas during spring, when phytoplankton production is enhanced and planktotrophic larvae may benefit from greater food availability

Hot topics in epigenetic regulation of cancer self-renewal for pancreatic tumors: future trends

Self-renewal is critical in order for a cancer to proliferate, grow and eventually metastasize. Today, several molecular mechanisms are being studied, which may explain the emergence of this property in advanced cancer. Pancreatic cancer is both a deadly and highly recurrent tumor, relying heavily on accelerated proliferation. Understanding self-renewal is this tumor type is therefore likely to prove essential for reaching better disease control. Recent advances in our understanding of telomere maintenance pathways are beginning to yield those insights. Indeed, it is now known that telomerase reactivation in cancer is intimately related with expression of TERT gene. The multimodal regulation of this locus, along with transcriptional output itself, both serve as prognostic factors across a variety of tumor types

Hot topics in epigenetic regulation of cancer self-renewal for pancreatic tumors: future trends

Self-renewal is critical in order for a cancer to proliferate, grow and eventually metastasize. Today, several molecular mechanisms are being studied, which may explain the emergence of this property in advanced cancer. Pancreatic cancer is both a deadly and highly recurrent tumor, relying heavily on accelerated proliferation. Understanding self-renewal is this tumor type is therefore likely to prove essential for reaching better disease control. Recent advances in our understanding of telomere maintenance pathways are beginning to yield those insights. Indeed, it is now known that telomerase reactivation in cancer is intimately related with expression of TERT gene. The multimodal regulation of this locus, along with transcriptional output itself, both serve as prognostic factors across a variety of tumor types