Perfil de expressão de microRNAs e análise computacional de vias moleculares moduladas por microRNAs em tumor carcinoide de pulmão
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Data
2019-01-28
Autores
Seneda, Ana Laura
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Universidade Estadual Paulista (Unesp)
Resumo
Introdução: O tumor carcinoide do pulmão pertence ao tipo neuroendócrino das neoplasias pulmonares. Devido à sua baixa incidência (~2%), pouco se conhece sobre suas alterações moleculares. Os microRNAs (miRNAs) têm importante papel na regulação gênica e têm sido associados ao câncer como biomarcadores diagnósticos, prognósticos e preditivos. Objetivos: Determinar o perfil global de expressão de miRNAs em tumores carcinoides do pulmão e identificar (in silico) vias moleculares envolvendo os miRNAs desregulados e genes-alvo preditos. Material e Métodos: Dois fragmentos de um tumor carcinoide típico e sua metástase correspondente foram obtidos, o RNA extraído de cada amostra e analisado na plataforma TaqMan Low Density Array (TLDA), a qual contém sondas para 384 miRNAs. Os dados foram analisados no Expression Suite software. Adicionalmente, 7 tumores (5 carcinoides típicos e 2 atípicos) foram utilizados para análise de expressão de 2,578 miRNAs na plataforma GeneChip™ miRNA 4.0 e os dados analisados utilizando o Transcriptome Analysis Console software. A análise estatística dos dados foi realizada para identificação dos miRNAs significativamente (p<0,05) alterados. Métodos de análise in silico incluíram a identificação de mRNAs-alvo dos miRNAs e vias moleculares de tumorigênese. Resultados e Discussão: No tumor carcinoide típico e metástase (TLDA), 15 miRNAs estavam com expressão comumente diminuída, os quais regulam genes associados a vias de resposta imune adaptativa. Adicionalmente, a comparação dos carcinoides típicos ou atípicos vs. normal (GeneChip arrays) resultou na identificação de 9 miRNAs desregulados em tumores típicos e 21 miRNAs em atípicos (p<0.01 and FDR<0.05). Em tumores típicos, os miRNAs modulam genes-alvo envolvidos na regulação do receptor FCƐRI, PDGF e NGF via TRKA. Nos tumores atípicos, os miRNAs alterados regulam genes associados à resposta imune inata e adaptativa e mecanismos de desenvolvimento e diferenciação neuronal. Conclusões: (1) a expressão diminuída de um conjunto específico de 15 miRNAs deve modular mecanismos de resposta imune e invasão associados ao desenvolvimento e progressão de um caso raro de carcinoide típico metastático; (2) os carcinoides típicos e atípicos apresentam diferentes perfis de expressão de miRNAs e vias moleculares de tumorigênese. Esses dados contribuem para o melhor entendimento de alterações em miRNAs e vias moleculares associadas aos tumores carcinoides de pulmão.
Introduction: Lung carcinoid tumors are a type of neuroendocrine lung neoplasia. Due to its low incidence (~2%), little is known about the molecular alterations associated with these tumors. microRNAs (miRNAs) have an important role in gene regulation and have been associated with cancer as diagnostic, prognostic and predictive biomarkers. Objectives: To determine the global expression miRNA profiles of lung carcinoid tumors and to identify (in silico) molecular pathways including deregulated miRNAs and predicted target-genes. Material and Methods: Two fragments of a typical carcinoid tumor and its corresponding metastasis were obtained, the RNA extracted and analyzed using the TaqMan Low Density Array (TLDA) platform containing 384 miRNAs. Data were analyzed using Expression Suite software. Additionally, 7 tumors (5 typical and 2 atypical carcinoids) were used for expression analysis of 2,578 miRNAs in the GeneChip™ miRNA 4.0 platform and data were analyzed using the Transcriptome Analysis Console software. Statistical analysis was performed to identify the significantly (p<0,05) deregulated miRNAs. In silico analyses methods included the identification of miRNA target genes (and enriched pathways. Results and Discussion: In the typical carcinoid tumor and metastasis (TLDA data), 15 miRNAs were commonly down-regulated and these modulate genes associated with the adaptive immune system pathway. Additionally, the comparison of typical carcinoids or atypical vs. normal (GeneChip arrays) showed 9 deregulated miRNAs in typical tumors and 21 miRNAs in atypical (p<0.01 and FDR<0.05).In typical tumors, identified miRNAs modulate the expression of target genes involved in the regulation of receptor FCƐRI, PDGF e NGF via TRKA. In the atypical tumors, altered miRNAs regulate genes with roles in adaptive and immune response and neuronal development and differentiation. Conclusions: (1) the 15 down-regulated miRNA subset may modulate mechanisms of immune response and invasion, associated with the development and progression in a rare case of metastatic carcinoid typical tumor; (2) typical and atypical lung carcinoids have different miRNA expression profiles and tumorigenesis pathways. These data contribute to our better understanding of miRNA alterations and pathways associated to lung carcinoid tumors.
Introduction: Lung carcinoid tumors are a type of neuroendocrine lung neoplasia. Due to its low incidence (~2%), little is known about the molecular alterations associated with these tumors. microRNAs (miRNAs) have an important role in gene regulation and have been associated with cancer as diagnostic, prognostic and predictive biomarkers. Objectives: To determine the global expression miRNA profiles of lung carcinoid tumors and to identify (in silico) molecular pathways including deregulated miRNAs and predicted target-genes. Material and Methods: Two fragments of a typical carcinoid tumor and its corresponding metastasis were obtained, the RNA extracted and analyzed using the TaqMan Low Density Array (TLDA) platform containing 384 miRNAs. Data were analyzed using Expression Suite software. Additionally, 7 tumors (5 typical and 2 atypical carcinoids) were used for expression analysis of 2,578 miRNAs in the GeneChip™ miRNA 4.0 platform and data were analyzed using the Transcriptome Analysis Console software. Statistical analysis was performed to identify the significantly (p<0,05) deregulated miRNAs. In silico analyses methods included the identification of miRNA target genes (and enriched pathways. Results and Discussion: In the typical carcinoid tumor and metastasis (TLDA data), 15 miRNAs were commonly down-regulated and these modulate genes associated with the adaptive immune system pathway. Additionally, the comparison of typical carcinoids or atypical vs. normal (GeneChip arrays) showed 9 deregulated miRNAs in typical tumors and 21 miRNAs in atypical (p<0.01 and FDR<0.05).In typical tumors, identified miRNAs modulate the expression of target genes involved in the regulation of receptor FCƐRI, PDGF e NGF via TRKA. In the atypical tumors, altered miRNAs regulate genes with roles in adaptive and immune response and neuronal development and differentiation. Conclusions: (1) the 15 down-regulated miRNA subset may modulate mechanisms of immune response and invasion, associated with the development and progression in a rare case of metastatic carcinoid typical tumor; (2) typical and atypical lung carcinoids have different miRNA expression profiles and tumorigenesis pathways. These data contribute to our better understanding of miRNA alterations and pathways associated to lung carcinoid tumors.
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Palavras-chave
Tumor carcinoide de pulmão, MicroRNAs, Sistema imune, Invasão, Vias neuronais, Lung carcinoid tumor, MicroRNAs, Immune system, Invasion, Neuronal pathways