Targeting miR‐31 represses tumourigenesis and dedifferentiation of BRAF<sup>V600E</sup>‐associated thyroid carcinoma
Peitao Zhang, Lizhao Guan, Wei Sun, Yu Zhang, Yaying Du, Shukai Yuan, Xiaolong Cao, Zhengquan Yu, Qiang Jia, Xiangqian Zheng, Zhaowei Meng, Xingrui Li, Li Zhao
Abstract
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 131 I 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 131 I uptake. Nanoparticle‐mediated application of anti‐miR‐31 antagomirs markedly elevated radio‐sensitivity of BRAF V600E ‐induced PTC tumours to 131 I 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.