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

作者：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 · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.1694 · 被引用次数：14 · 研究领域：Thyroid Cancer Diagnosis and Treatment、Cancer-related Molecular Pathways、Biomarkers in Disease Mechanisms

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 ...