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Hsa‐miR‐139‐5p is a prognostic thyroid cancer marker involved in HNRNPF‐mediated alternative splicing

2019; Wiley; Volume: 146; Issue: 2 Linguagem: Inglês

10.1002/ijc.32622

1097-0215

Cristina Montero‐Conde, Osvaldo Graña‐Castro, Guillermo Martín‐Serrano, Ángel M. Martínez‐Montes, Eduardo Zarzuela, Javier Muñoz, Rafael Torres‐Pérez, Guillermo Pita, Alfonso Cordero‐Barreal, Luis J. Leandro‐García, Rocío Letón, Isabel López de Silanes, Sonsoles Guadalix, Andrés Pérez‐Barrios, Federico Hawkins, Almudena Guerrero‐Álvarez, Cristina Álvarez‐Escolá, Rita María Regojo, Bruna Calsina, Laura Remacha, Juan María Roldán‐Romero, María Santos, Javier Lanillos, Mireia Jordà, Garcilaso Riesco‐Eizaguirre, Carles Zafón, Anna González‐Neira, Marı́a A. Blasco, Fátima Al‐Shahrour, Cristina Rodríguez‐Antona, Alberto Cascón, Mercedes Robledo,

MicroRNA in disease regulation

It is critical to identify biomarkers and functional networks associated with aggressive thyroid cancer to anticipate disease progression and facilitate personalized patient management. We performed miRNome sequencing of 46 thyroid tumors enriched with advanced disease patients with a median follow‐up of 96 months. MiRNome profiles correlated with tumor‐specific histopathological and molecular features, such as stromal cell infiltration and tumor driver mutation. Differential expression analysis revealed a consistent hsa‐miR‐139‐5p downexpression in primary carcinomas from patients with recurrent/metastatic disease compared to disease‐free patients, sustained in paired local metastases and validated in publicly available thyroid cancer series. Exogenous expression of hsa‐miR‐139‐5p significantly reduced migration and proliferation of anaplastic thyroid cancer cells. Proteomic analysis indicated RICTOR, SMAD2/3 and HNRNPF as putative hsa‐miR‐139‐5p targets in our cell system. Abundance of HNRNPF mRNA, encoding an alternative splicing factor involved in cryptic exon inclusion/exclusion, inversely correlated with hsa‐miR‐139‐5p expression in human tumors. RNA sequencing analysis revealed 174 splicing events differentially regulated upon HNRNPF repression in our cell system, affecting genes involved in RTK/RAS/MAPK and PI3K/AKT/MTOR signaling cascades among others. These results point at the hsa‐miR‐139‐5p/HNRNPF axis as a novel regulatory mechanism associated with the modulation of major thyroid cancer signaling pathways and tumor virulence.