Targeting miR-31 represses tumourigenesis and dedifferentiation of BRAF^V600E-associated thyroid carcinoma

Abstract

Background: BRAF^V600E is the most common genetic mutation in differentiated thyroid cancer (DTC) occurring in 60% of patients and drives malignant tumour cell phenotypes including proliferation, metastasis and immune-escape. BRAF^V600E-mutated papillary thyroid cancer (PTC) also displays greatly reduced expression of thyroid differentiation markers, thus tendency to radioactive iodine (RAI) refractory and poor prognosis. Therefore, understanding the molecular mechanisms and main oncogenic events underlying BRAF^V600E will guide future therapy development.

Methods: Bioinformatics and clinical specimen analyses, genetic manipulation of BRAF^V600E-induced PTC model, functional and mechanism exploration guided with transcriptomic screening, as well as systematic rescue experiments were applied to investigate miR-31 function within BRAF^V600E-induced thyroid cancer development. Besides, nanoparticles carrying miR-31 antagomirs were testified to alleviate ¹³¹I iodide therapy on PTC models.

Results: We identify miR-31 as a significantly increased onco-miR in BRAF^V600E-associated PTC that promotes tumour progression, metastasis and RAI refractoriness via sustained Wnt/β-catenin signalling. Mechanistically, highly activated BRAF/MAPK pathway induces miR-31 expression via c-Jun-mediated transcriptional regulation across in vitro and transgenic mouse models. MiR-31 in turn facilitates β-catenin stabilisation via directly repressing tumour suppressors CEBPA and DACH1, which direct the expression of multiple essential Wnt/β-catenin pathway inhibitors. Genetic functional assays showed that thyroid-specific knockout of miR-31 inhibited BRAF^V600E-induced PTC progression, and strikingly, enhanced expression of sodium-iodide symporter and other thyroid differentiation markers, thus promoted ¹³¹I uptake. Nanoparticle-mediated application of anti-miR-31 antagomirs markedly elevated radio-sensitivity of BRAF^V600E-induced PTC tumours to ¹³¹I therapy, and efficiently suppressed tumour progression in the pre-clinical mouse model.

Conclusions: Our findings elucidate a novel BRAF/MAPK-miR-31-Wnt/β-catenin regulatory mechanism underlying clinically BRAF^V600E-associated DTC tumourigenesis and dedifferentiation, also highlight a potential adjuvant therapeutic strategy for advanced DTC.

Keywords

BRAF ^V600E / CEBPA / DACH1 / miR-31 / papillary thyroid carcinoma / Wnt/β-catenin pathway

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2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.