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Hsa‐miR‐139‐5p is a prognostic thyroid cancer marker involved in HNRNPF‐mediated alternative splicing
Author(s) -
MonteroConde Cristina,
GrañaCastro Osvaldo,
MartínSerrano Guillermo,
MartínezMontes Ángel M.,
Zarzuela Eduardo,
Muñoz Javier,
TorresPerez Rafael,
Pita Guillermo,
CorderoBarreal Alfonso,
LeandroGarcía Luis J.,
Letón Rocío,
López de Silanes Isabel,
Guadalix Sonsoles,
PérezBarrios Andrés,
Hawkins Federico,
GuerreroÁlvarez Almudena,
ÁlvarezEscolá Cristina,
RegojoZapata Rita M.,
Calsina Bruna,
Remacha Laura,
RoldánRomero Juan M.,
Santos María,
Lanillos Javier,
Jordá Mireia,
RiescoEizaguirre Garcilaso,
Zafon Carles,
GonzálezNeira Anna,
Blasco Maria A.,
AlShahrour Fátima,
RodríguezAntona Cristina,
Cascón Alberto,
Robledo Mercedes
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32622
Subject(s) - thyroid cancer , cancer research , biology , pi3k/akt/mtor pathway , thyroid , microrna , alternative splicing , cancer , stromal cell , anaplastic thyroid cancer , exon , signal transduction , gene , genetics
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.