碘对甲状腺乳头状癌预后转归的影响极其分子机制研究

The thyroid papillary carcinoma (PTC) has a rapidly increasing incidence, high prevalence rate and high recurrence rate. The study suggests that iodine may be associated with prognosis in patients with PTC. Iodine has been added to make most residents in iodine sufficient or over-full status. It’s significantly to study the relationship between iodine and the prognosis of PTC. Our previous study found that cell autophagy mediated the effects of iodine on the proliferation, apoptosis and migration of PTC cells,and have unique autophagy related signaling pathways. Our project through aspects as follows：1.The relationship between iodine and the outcome of PTC was determined by population, tissue and cell research；2. Based on the method of RNA-seq sequencing and bioinformatics molecular network analysis, and using PTC cells to screen the differentially expressed genes and pathways that iodine affect the biological behavior, and verify and optimize the candidate genes by qRT-PCR; Knockout or overexpression of candidate genes in the model to animal and cells, observe the iodine on PTC cells and tumor. Observe the expression pattern of candidate genes in the cancer tissues of PTC patients under different iodine exposure conditions ,and identify the main effect genes.3. Give targeted treatment to tumor mice by targeting drugs of the main effect gene, study on the changes of tumor characteristics and main effect gene expression after different iodine feeding. To find a reasonable and accurate iodine intake for patients with PTC, and to provide the evidence for preventing recurrence and deterioration.

甲状腺乳头状癌（PTC）发病率增长快,患病率高、复发率高。研究提示碘可能与PTC的预后转归相关，补碘已使多数居民处于碘适量或超足量状态，所以研究碘与PTC预后转归的关系意义重大。我们前期研究发现细胞自噬介导碘影响PTC细胞增殖、凋亡和迁移,具有独特的自噬相关信号通路。本项目：1. 通过人群、组织和细胞实验明确碘与PTC预后结局的关系；2.基于RNA-seq测序和生物信息学分子网络分析方法，利用PTC细胞筛选碘影响其生物学行为的差异表达基因及通路，通过qRT-PCR验证、优选候选基因；敲除或过表达PTC细胞、动物成瘤模型候选基因,观察碘对PTC细胞、瘤体的影响，并确认不同碘暴露条件下PTC患者癌组织中候选基因的表达模式，进而明确主效基因；3.利用针对主效基因的小分子化合物处理成瘤鼠，研究不同碘喂养后瘤体特征和主效基因表达的变化。从而为PTC患者寻找最佳的碘摄入量，防止其复发和恶化提供依据。

近年来，甲状腺乳头状癌（PTC）由于淋巴结转移和复发的比例较高，其发病率不断上升，给个人和社会带来了沉重的医疗负担。碘可能引发甲状腺癌的发生和发展，但其相关机制尚不清楚。众所周知，环状RNA（circRNAs）可以作为竞争性内源性RNA（ceRNAs）调控基因转录，参与了癌症进展的各个阶段。然而，关于circRNA在碘诱导甲状腺癌发展中的作用鲜有报道。在这项研究中，我们通过对适碘及高碘PTC组织样本进行了全转录组深度测序，获得差异表达基因，并构建circ RNA-mi RNA-mRNA基因相互作用网络，探讨circRNA参与碘在PTC发展中的机制。研究发现circ _0004851(circ CAPRIN1)可充当miR-296-3p的海绵，并减轻对靶基因FGF11的抑制，从而参与碘对PTC的影响。circ _0004851沉默与PTC在体内和体外凋亡、迁移、侵袭和增殖的可能性直接相关。荧光原位杂交（FISH）进一步用于确认circ _0004851的细胞质定位，表明circ _0004851可能通过miRNA结合在PTC进展中作为ceRNAs发挥作用。然后通过荧光素酶报告分析证实MiR-296-3p受circ _0004851调控，并靶向FGF11。在PTC中进一步研究了miR-296-3p的抗肿瘤作用和FGF11的促肿瘤作用，表明circ _0004851通过miR-296-3p/FGF11途径调节PTC的进展。总之，我们的结果表明，circ _0004851/miR-296-3p/FGF11轴参与了高碘暴露的PTC发展，并为碘影响PTC进展提供了一种潜在有效的治疗策略。