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Int J Cancer. 2019 Aug 12. doi: 10.1002/ijc.32622. [Epub ahead of print]

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

Author information

1
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
2
Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
3
Proteomics Core Unit and Proteored-ISCIII, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
4
CEGEN Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
5
Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
6
Endocrinology and Nutrition Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
7
Anatomical Pathology Section, Hospital Universitario 12 de Octubre, Madrid, Spain.
8
Endocrinology and Nutrition Department, Madrid, Spain.
9
Anatomical Pathology Section Hospital Universitario La Paz, Madrid, Spain.
10
Program for Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute, Barcelona, Spain.
11
Endocrinology and Nutrition Department, Hospital Universitario de Móstoles, Madrid, Spain.
12
Biomedical Research Networking Centre in Oncology (CIBERONC), Institute of Health Carlos III, Madrid, Spain.
13
Universidad Francisco de Vitoria, Madrid, Spain.
14
Diabetes and Metabolism Research Unit and Endocrinology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
15
Biomedical Research Networking Centre on Diabetes and Associated Metabolic Diseases (CIBERDEM), Institute of Health Carlos III, Madrid, Spain.
16
Biomedical Research Networking Centre on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain.

Abstract

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.

KEYWORDS:

hsa-miR139-5p and HNRNPF; miRNome sequencing; stroma infiltration; thyroid cancer

PMID:
31403184
DOI:
10.1002/ijc.32622

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