RESUMEN
The objective of the study was to identify the deregulated miRNA in autonomous adenoma and to correlate the data with mRNA regulation. Seven autonomous adenoma with adjacent healthy thyroid tissues were investigated. Twelve miRNAs were downregulated and one was upregulated in the tumors. Combining bioinformatic mRNA target prediction and microarray data on mRNA regulations allowed to identify mRNA targets of our deregulated miRNAs. A large enrichment in mRNA encoding proteins involved in extracellular matrix organization and different phosphodiesterases were identified among these putative targets. The direct interaction between miR-101-3p and miR-144-3p and PDE4D mRNA was experimentally validated. The global miRNA profiles were not greatly modified, confirming the definition of these tumors as minimal deviation tumors. These results support a role for miRNA in the regulation of extracellular matrix proteins and tissue remodeling occurring during tumor development, and in the important negative feedback of the cAMP pathway, which limits the consequences of its constitutive activation in these tumors.
Asunto(s)
Adenoma/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , MicroARNs/genética , ARN Mensajero/genética , Neoplasias de la Tiroides/genética , Adenoma/metabolismo , Adenoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , ARN Mensajero/metabolismo , Transducción de Señal/genética , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Análisis de Matrices TisularesRESUMEN
BACKGROUND: For thyroid tumorigenesis, two main human in vitro models are available: primary cultures of human thyrocytes treated with TSH or EGF/serum as models for autonomous adenomas (AA) or papillary thyroid carcinomas (PTC) respectively, and human thyroid tumor derived cell lines. Previous works of our group have assessed properties of those models, with a special emphasis on mRNA regulations. It is often assumed that miRNA may be one of the primary events inducing these mRNA regulations. METHODS: The purpose of this study was to investigate the representativity of those models to study microRNA regulations and their relation with mRNA expression. To achieve this aim, the miRNA expressions profiles of primary cultures treated with TSH or EGF/serum and of 6 thyroid cancer cell lines were compared to the expression profiles of 35 tumor tissues obtained by microarrays. RESULTS: Our data on primary cultures have shown that the TSH or EGF/serum treatment did not greatly modify the microRNA expression profiles, which is contrary to what is observed for mRNA expression profiles, although they still evolved differently according to the treatment. The analysis of miRNA and mRNA expressions profiles in the cell lines has shown that they have evolved into a common, dedifferentiated phenotype, closer to ATC than to the tumors they are derived from. CONCLUSIONS: Long-terms TSH or EGF/serum treatments do not mimic AA or PTC respectively in terms of miRNA expression as they do for mRNA, suggesting that the regulations of mRNA expression induced by these physiological agents occur independently of miRNA. The general patterns of miRNA expression in the cell lines suggest that they represent a useful model for undifferentiated thyroid cancer. Mirna probably do not mediate the rapid changes in gene expression in rapid cell biology regulation.
Asunto(s)
Carcinoma Papilar/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , MicroARNs/genética , ARN Mensajero/genética , Neoplasias de la Tiroides/genética , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Factor de Crecimiento Epidérmico/farmacología , Humanos , MicroARNs/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/metabolismo , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Glándula Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Tirotropina/farmacologíaRESUMEN
In two landmark articles, Hanahan and Weinberg synthesized into one conceptual framework 'the hallmarks of cancer', a massive amount of information describing the characteristics of a cancer cell. Although this is neither the intention nor the belief of the authors, hallmarks are often interpreted as applying to a canonic cancer cell, or equally to all cells within a cancer. In this article, we clarify the separate concepts of causes, oncogenic events, signal transduction programs, and hallmarks to show that there is no unimodal relation between these concepts but a complex network of interrelations that vary in different cells, between cells, and at different times in any given cell. We consider cancer as an evolving, dynamic, and heterogeneous system, explaining, at least in part, the difficulty of treating cancer and supporting the use of simultaneous, multitarget therapies.
