长链非编码RNA TINCR新异构体在甲状腺乳头状癌中的鉴定及功能机制研究

Thyroid cancer has become the fastest growing malignant tumor, the main type of which is papillary thyroid carcinoma (PTC). Its pathogenesis needs to be clarified urgently. Long non-coding RNA (lncRNA) plays an important role in tumorigenesis and development, and has great potential application value in the diagnosis and treatment of PTC. TINCR is a key lncRNA in epithelial differentiation, which plays a role in the tumorigenesis and metastasis of various malignant tumors. The functional mechanism of TINCR is not yet clear. We originally identified a novel isoform of TINCR, named lncTR. We found that lncTR can bind to RNA binding protein STAU1 in PTC. Importantly, lncTR was positively correlated with tumor size, down-regulation of lncTR can induce cell cycle arrest and inhibit the proliferation of tumors, suggesting that lncTR has potential tumorigenesis effect in PTC. This project intends to construct a cell and animal research model involving lncTR knockdown or overexpression, and systematically study the effects of lncTR on the biological function of PTC tumors. Further, we will study the molecular mechanism that lncTR regulates PTC tumorigenesis by RNA immunoprecipitation, proteomics and transcriptome sequencing. Uncovering the mechanism of lncTR will open a new field for the study of the functional mechanism of TINCR, and provide theoretical basis and potential therapeutic targets for the clinical diagnosis and treatment of PTC.

甲状腺癌已成为发病率增长最快的恶性肿瘤，主要类型为乳头状癌（PTC），其发病机制亟待阐明。长链非编码RNA（lncRNA）在肿瘤发生发展中扮演着重要角色，在PTC诊断治疗中极具应用价值。TINCR是一种在表皮分化中关键的lncRNA，在多种肿瘤中发挥作用，功能机制尚未明确。我们在PTC中原创性地鉴定TINCR的新异构体lncTR，发现lncTR能与RNA结合蛋白STAU1结合。重要的是，lncTR与肿瘤大小正相关，其下调可引起细胞周期阻滞，抑制肿瘤增殖，提示lncTR在PTC中具有潜在的促癌作用。本项目在前期基础上，构建lncTR敲低或过表达的细胞及动物研究模型，系统研究lncTR对PTC生物学功能影响；进一步采用RNA免疫共沉淀、蛋白质/转录组学等技术深入研究lncTR调控PTC发生的分子机制，这将为TINCR功能机制研究打开新的突破口，为PTC临床诊断治疗提供理论依据和潜在治疗靶点。

甲状腺癌是最常见的内分泌系统恶性肿瘤，其中甲状腺乳头状癌（PTC）发病率在全球范围内呈明显快速上升趋势。长链非编码RNA (lncRNA)是一种长度超过200个核苷酸的非编码RNA，已有大量的研究显示lncRNA在甲状腺癌中发挥重要作用。因此，进一步深入研究lncRNA在PTC中的作用机制，将为甲状腺乳头状癌的诊断、治疗及预后监测提供新的理论依据。在本研究中，我们旨在探索TINCR新异构体在甲状腺乳头状癌中的作用和潜在机制。我们发现lncTR是TINCR的一个新型异构体，与TINCR迥异，lncTR无蛋白编码能力，并主要定位在细胞核中。lncTR在甲状腺乳头状癌中高表达，与肿瘤T分期以及不良的预后生存相关。在功能上，lncTR在体内体外都可以促进肿瘤细胞的增殖并维持肿瘤细胞的干性。在机制上，我们发现lncTR可以通过调控Hedgehog信号通路来维持肿瘤细胞的干性，此外lncTR还可以介导PTC细胞的放疗抵抗。lncTR在核内触发了HDAC1-Hedgehog信号轴，我们推断lncTR通过引导HDAC1对Hedgehog通路关键转录因子Gli家族进行去乙酰化并激活Hedgehog通路。综上所述，lncTR可以通过Hedgehog信号通路维持肿瘤细胞的干性并介导放疗抵抗，为甲状腺乳头状癌提供了有效的预后指标和治疗靶标。