转录因子ETV7招募c-Jun调控上皮间质可塑性促进BRAF V600E突变型甲状腺乳头状癌转移的机制研究

BRAF V600E是甲状腺乳头状癌（PTC）最常见突变，赋予PTC高转移能力、增加复发转移风险，但机制不明。我们首次应用CRISPR/Cas9技术在全基因组范围筛选出调控BRAF V600E突变型PTC细胞转移的关键转录因子ETV7，并证明ETV7通过调控上皮间质可塑性促进BRAF V600E突变型PTC转移。预实验还发现BRAF V600E能激活MAPK/ERK磷酸化c-Jun，后者经ETV7招募形成ETV7/c-Jun复合物而促进EMT诱导转录因子（EMT-TFs）转录。为此，本研究提出ETV7招募c-Jun增强EMT-TFs表达来调控BRAF V600E突变型PTC细胞的上皮间质可塑性而促进转移的科学假设，并将深入揭示ETV7招募c-Jun调控PTC转移的分子机制、探讨靶向ETV7联合BRAF V600E抑制PTC转移的疗效，为ETV7作为PTC转移生物标志物和治疗靶点提供依据。

BRAF V600E is the most common mutation in papillary thyroid cancer (PTC), which confers high metastatic ability to PTC, increases high risks of recurrence and metastasis, but with unknown molecular mechanisms. Herein, we utilized genome-wide CRISPR screen to identified transcription factor ETV7 as a key regulator that promotes BRAF V600E PTC cells metastasis by regulating epithelial-mesenchymal plasticity (EMP). We also found that ETV7 could recruit c-Jun, which phosphorylated by BRAF V600E activated MAPK/ERK cascade, to form ETV7/c-Jun complex and induce the transcription of EMT-inducing transcription factors (EMT-TFs). Thus, we propose the scientific hypothesis that ETV7 recruits c-Jun to enhance the transcription of EMT-TFs and regulates the epithelial mesenchymal plasticity of BRAF V600E PTC cells to maintain highly metastatic ability. We are going to explore the molecular mechanism of ETV7 recruiting c-Jun to promote the metastasis of BRAF V600E PTC cells, clarify the effectiveness of targeting ETV7 combined with BRAF V600E inhibitor to inhibit the metastasis of PTC cells, and provide a theoretical basis for ETV7 as a metastatic biomarker and therapeutic target for PTC.