MicroRNoma do carcinoma de pâncreas

Background: Genetic alterations were previously identified and associated with the development and progression of pancreatic carcinoma, however, identification of such alterations has not been currently used for the development of efficient treatment strategies. Therefore, the identification of other genetic and epigenetic changes, such as alterations in non-coding RNA molecules is urgently needed for the development of novel therapies. Recent studies have suggested that microRNAs (miRNAs) are frequently deregulated in several carcinomas and may contribute in the several steps of development and tumor progression. Global miRNA profiling analysis in pancreatic carcinoma and the identification of miRNA target genes may lead to new avenues for the identification of clinically applicable biomarkers. Objectives: To identify global microRNA (miRNA) expression profiles and miRNA predicted target genes in pancreatic carcinoma. Patients and Methods: 30 formalin fixed, paraffin embedded (FFPE) pancreatic carcinoma tissue samples were used, including 24 pancreatic ductal adenocarcinoma (PDAC) and 6 adenocarcinomas of Vater papilla (AMP) and their paired histologically adjacent normal tissues. Global miRNA expression profiles were determined using the TaqMan Array Human MicroRNA Cards (TLDA) (card A, v3.0) (Life Technologies) platform. Data analysis used the ExpressionSuite Software v1.0.3. Statistical analysis was performed to correlate miRNA expression with relevant clinical data, using SAS 9.3 software. Computational bioinformatic analysis was performed to identify predicted miRNA target genes, as well as protein-protein interaction networks and miRNA-mRNA molecular pathways. Results: We identified 63 significantly deregulated (significantly deregulated is herein defined as FC≥2 and p<0.05) miRNAs in PDAC (33 over-expressed and 30 under-expressed) compared to paired histologically normal pancreatic tissue. In AMP, a group of 7 miRNAs was significantly deregulated (4 over-expressed and 3 under-expressed) compared to normal. Our results showed a complexity of miRNAs changes potentially associated to PDAC tumorigenesis. Interestingly, 3/7 miRNAs were commonly deregulated in PDAC and AMP tumors. Discussion: Global miRNA expression profiles identified in PDAC and AMP showed that PDAC have a significantly higher number of altered miRNAs and consequently, a higher number of predicted miRNA target genes than AMP, which could be potentially associated to disease progression and tumor aggressiveness in PDAC compared to AMP. Commonly deregulated miRNAs in PDAC and AMP suggest that common molecular pathways may be deregulated in these two histological subtypes of pancreatic carcinoma. Among the miRNAs exclusively deregulated in PDAC, we identified several predicted miRNA target genes associated to tumor invasion and metastasis and poor prognosis of patients with cancer. Conclusion: miRNAs identified herein may be associated to the biology of PDAC and AMP. Functional validation studies are required to elucidate the role of miRNAs as modulators of oncogenesis mechanisms in PDAC and AMP.Introdução: Alterações genéticas foram previamente identificadas e associadas ao desenvolvimento e progressão dos carcinomas pancreáticos, entretanto, o conhecimento dessas alterações não resultou, até o momento, no desenvolvimento de tratamentos eficazes para os pacientes com essas neoplasias. Sendo assim, torna-se necessária e justificada a identificação de outras alterações, tais como alterações em moléculas reguladoras da expressão gênica, as quais têm o potencial de levar ao delineamento de novas terapias. Estudos recentes têm sugerido que os microRNAs (miRNAs) estão frequentemente desregulados em diversos carcinomas, e podem contribuir em várias etapas do desenvolvimento e progressão tumoral. A análise do perfil de expressão de miRNAs em carcinomas de pâncreas e genes regulados por estes miRNAs, deve fornecer novas direções para a identificação de biomarcadores que possam ser úteis na prática clínica. Objetivos: Identificar perfis globais de expressão de microRNAs (miRNAs) e potenciais genes-alvo regulados por miRNAs em carcinomas de pâncreas. Pacientes e Métodos: Foram incluídas 30 amostras de tecido, fixadas em formalina e emblocadas em parafina (FFPE) de carcinoma de pâncreas, sendo 24 adenocarcinomas de ductos pancreáticos (PDAC) e 6 adenocarcinomas de papila de Vater (AMP) e os tecidos histologicamente normais, adjacentes ao tumor, correspondentes a cada caso. O perfil de expressão de miRNAs das amostras tumorais foi determinado utilizando o ensaio TaqMan Array Human MicroRNA Cards (TLDA) (card A, v3.0) (Life Technologies). A análise dos dados utilizou o programa ExpressionSuite Software v1.0.3. A análise estatística dos dados de expressão de miRNAs e dados clínico-anatomopatológicos utilizou o programa SAS 9.3. Análises computacionais utilizando algorítimos de bioinformática foram realizadas com o objetivo de identificar genes-alvo regulados por miRNAs, bem como redes de interação protéica e vias moleculares envolvendo genes e miRNAs. Resultados: Foram identificados 63 miRNAs desregulados em PDAC, sendo 33 com expressão aumentada e 30 com expressão diminuída, quando comparado com tecido histologicamente normal adjacente ao tumor. Nos carcinomas AMP, um grupo de 7 miRNAs estavam desregulados, sendo 4 com expressão aumentada e 3 com expressão diminuída. Nossos resultados indicam uma complexidade de alterações associadas à tumorigênese dos adenocarcinomas ductais pancreáticos, devido ao grande número de miRNAs e genes-alvo desregulados nesses tumores. Interessantemente, 3/7 miRNAs identificados como desregulados em carcinomas AMP estão comumente alterados nos PDAC. Discussão: O perfil de expressão global de miRNAs identificado em PDAC e carcinomas AMP revelou que os PDACs apresentam um número significativamente maior de miRNAs desregulados, o que pode estar diretamente associado a um maior grau de progressão e maior agressividade tumoral comparado com os carcinomas AMP. A identificação de 3 miRNAs comumente alterados em PDAC e carcinomas AMP sugere que vias moleculares comuns podem estar desreguladas nesses subtipos histológicos tumorais. Dentre os miRNAs alterados exclusivamente nos PDACs, identificamos que esses regulam vários genes associados à invasão tecidual, metástase e pior prognóstico de pacientes com câncer. Conclusão: Os miRNAs identificados estão potencialmente associados à biologia tumoral dos PDAC e carcinomas AMP. Estudos de validação funcional são necessários para elucidar o papel dos miRNAs como moduladores de mecanismos de oncogênese em PDAC e carcinomas AMP.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Deciphering Key microRNA Regulated Pathways in Tissue-Engineered Blood Vessels: Implications for Vascular Scaffold Production

MicroRNAs (miRNAs) are non-coding RNAs involved in the regulation of gene expression associated with cell differentiation, proliferation, adhesion, and important biological functions such as inflammation. miRNAs play roles associated with the pathogenesis of chronic degenerative disorders including cardiovascular diseases. Understanding the influence of miRNAs and their target genes can effectively streamline the identification of key biologically active pathways that are important in the development of vascular grafts through the tissue engineering of blood vessels. To determine miRNA expression levels and identify miRNA target genes and pathways with biological roles in scaffolds that have been repopulated with adipose-derived stem cells (ASCs) generated through tissue engineering for the construction of blood vessels. miRNA quantification assays were performed in triplicate to determine miRNA expression in a total of 20 samples: five controls (natural inferior vena cava), five scaffolds recellularized with ASCs and differentiated into the endothelium (luminal layer), five samples of complete scaffolds seeded with ASCs differentiated into the endothelium (luminal layer) and smooth muscle (extraluminal layer), and five samples of ASC without cell differentiation. Several differentially expressed miRNAs were identified and predicted to modulate target genes with roles in key pathways associated with angiogenesis, vascular system control, and endothelial and smooth muscle regulation, including migration, proliferation, and growth. These findings underscore the involvement of these pathways in the regulatory mechanisms that are essential for vascular scaffold production through tissue engineering. Our research contributes to the knowledge of miRNA-regulated mechanisms, which may impact the design of vascular substitutes, and provide valuable insights for enhancing clinical practice. The molecular pathways regulated by miRNAs in tissue engineering of blood vessels (TEBV) allowed us to elucidate the main phenomena involved in cellular differentiation to constitute a blood vessel, with the main pathways being essential for angiogenesis, cellular differentiation, and differentiation into vascular smooth muscle

Advances in the Molecular Landscape of Lung Cancer Brain Metastasis

Lung cancer is one of the most frequent tumors that metastasize to the brain. Brain metastasis (BM) is common in advanced cases, being the major cause of patient morbidity and mortality. BMs are thought to arise via the seeding of circulating tumor cells into the brain microvasculature. In brain tissue, the interaction with immune cells promotes a microenvironment favorable to the growth of cancer cells. Despite multimodal treatments and advances in systemic therapies, lung cancer patients still have poor prognoses. Therefore, there is an urgent need to identify the molecular drivers of BM and clinically applicable biomarkers in order to improve disease outcomes and patient survival. The goal of this review is to summarize the current state of knowledge on the mechanisms of the metastatic spread of lung cancer to the brain and how the metastatic spread is influenced by the brain microenvironment, and to elucidate the molecular determinants of brain metastasis regarding the role of genomic and transcriptomic changes, including coding and non-coding RNAs. We also present an overview of the current therapeutics and novel treatment strategies for patients diagnosed with BM from NSCLC

Advances in the Molecular Landscape of Lung Cancer Brain Metastasis

Lung cancer is one of the most frequent tumors that metastasize to the brain. Brain metastasis (BM) is common in advanced cases, being the major cause of patient morbidity and mortality. BMs are thought to arise via the seeding of circulating tumor cells into the brain microvasculature. In brain tissue, the interaction with immune cells promotes a microenvironment favorable to the growth of cancer cells. Despite multimodal treatments and advances in systemic therapies, lung cancer patients still have poor prognoses. Therefore, there is an urgent need to identify the molecular drivers of BM and clinically applicable biomarkers in order to improve disease outcomes and patient survival. The goal of this review is to summarize the current state of knowledge on the mechanisms of the metastatic spread of lung cancer to the brain and how the metastatic spread is influenced by the brain microenvironment, and to elucidate the molecular determinants of brain metastasis regarding the role of genomic and transcriptomic changes, including coding and non-coding RNAs. We also present an overview of the current therapeutics and novel treatment strategies for patients diagnosed with BM from NSCLC