近年来我国甲状腺癌发病率增长迅猛，其中家族性甲状腺非髓样癌（FNMTC）每年新增病例约2.2万，发病机制不清。课题组前期基于FNMTC临床队列的全外显子组测序结果提示CLIP1是FNMTC的易感基因。预实验发现：在甲状腺滤泡上皮细胞中，CLIP1敲低和过表达均会导致有丝分裂不同阶段的阻滞，并促进肿瘤关键事件：染色体不稳定（CIN）和异倍体的出现。基于文献和工作基础，我们提出：CLIP1的精准调控对维持甲状腺滤泡上皮细胞染色体稳定性具有重要作用，CLIP1突变导致蛋白异常失活/激活均可促进肿瘤的发生。本项目拟采用慢病毒、Crispr/Cas9构建CLIP1过表达/低表达/突变的甲状腺稳定细胞株，结合临床肿瘤样本，确定CLIP1异常导致有丝分裂阻滞、CIN和异倍体的现象，并探究分子机制。本项目将阐明CLIP1突变携带者甲状腺肿瘤发病的分子机制，揭示潜在治疗靶点，提出针对高危人群的防控策略。

The incidence of thyroid cancer increases dramatically in recent years. The number of newly diagnosed familial non-medullary thyroid cancer (FNMTC) reaches to approximately 22,000 annually in China, while the mechanism remains elusive. Previously we identified the cytoplasmic linker protein 1 (CLIP1) as a germline susceptible gene in FNMTC by conducting whole genome sequencing in clinical samples, but the functional role of this gene in thyroid carcinogenesis has not been studied. Our preliminary data suggest that both under- and over-expression of CLIP1 in thyroid follicular epithelial cells resulted in cell cycle arrest, chromosomal instability (CIN) and aneuploidy. Both CIN and aneuploidy are considered as key events for tumorigenesis. Based on former studies and our data, we propose that precise regulation of CLIP1 gene expression contributes to maintaining chromosomal stability, and the abnormal protein activation/inactivation caused by gene mutations promote thyroid oncogenesis. This project aims to validate the functional roles of CLIP1 in regulating cell cycle, CIN and aneuploidy, and to explore the underlying molecular mechanisms. Stable thyroid epithelial cell lines with CLIP1 knockdown/overexpression/mutations constructed by lentivirus and Crispr/Cas9 system and clinical samples will be utilized in this project. The scientific significance of this study is to elucidate the involvement of CLIP1 in thyroid tumorigenesis for the first time and hence provide new perspectives for tumor prevention and therapeutic targets development.