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

Autor: Zhang P; Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China., Guan L; Department of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China.; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China., Sun W; Laboratory of molecular genetics, School of Medicine, Nankai University, Tianjin, China., Zhang Y; Department of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China.; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China., Du Y; Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China., Yuan S; Department of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China.; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China., Cao X; Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China., Yu Z; State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China., Jia Q; Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China., Zheng X; Department of Thyroid and Neck Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China., Meng Z; Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China., Li X; Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China., Zhao L; Department of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China.; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
Jazyk: angličtina
Zdroj: Clinical and translational medicine [Clin Transl Med] 2024 May; Vol. 14 (5), pp. e1694.
DOI: 10.1002/ctm2.1694
Abstrakt: 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.
(© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Databáze: MEDLINE
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