miR-151-5p促进甲状腺乳头状癌侵袭转移的作用及机制研究

Thyroid papillary cancer is the most common endocrine-related cancer, of which death risk factors include lymph node or distant metastasis. In our previous study, expression of miR-151-5p was found significantly elevated in serum and tissue of patients with papillary thyroid cancer (PTC); In addition, miR-151-5p expression positively correlates lymph node metastasis and TNM stage, indicating that miR-151-5p is associated with proliferation, invasion and metastasis of PTC. we speculate that miR-151-5p expressed together with its host gene FAK, inducing proliferation, invasion and metastasis of thyroid cancer through THRB-PI3K-AKT-mTOR signal pathway.To prove this speculation, in vitro and in vivo studies involving cell proliferation assay, invasion and migration assay and signaling pathway experiments will be performed to verify that 1) the role of miR-151-5p in proliferation, invasion and metastasis of thyroid cancer;2) the mechanism underlying differential expression of miR-151-5p, and miR-151-5p regulates thyroid cancer through THRB-PI3K-AKT-mTOR signal pathway; 3)the corelation of the miR-151-5p target role and THRB mutation.The completion of this study will for the first time clarify the important role of miR-222 in thyroid cancer and hopefully provide a new therapeutic target.

甲状腺乳头状癌(PTC)是最常见的内分泌恶性肿瘤，死亡危险因素包括淋巴结及远处转移。我们的前期研究发现PTC患者血清及组织中miR-151-5p表达明显升高，其表达与淋巴结转移及TNM分期呈正相关，提示miR-151-5p与PTC增殖、侵袭转移相关。我们推测在PTC中miR-151-5p与FAK共表达，通过调节THRB基因影响PI3K- AKT-mTOR信号通路诱导PTC增殖及侵袭转移。本课题拟通过体内外肿瘤细胞增殖、侵袭转移实验和信号通路上下游调控实验，获得miR-151-5p调控PTC增殖以及侵袭转移的证据；探索miR-151-5p在PTC中差异表达机制，阐明THRB-PI3K-AKT-mTOR信号通路在miR-151-5p调控PTC中的作用；探讨miR-151-5p靶向作用及THRB基因突变的相关性。本研究将首次阐明miR-151-5p在PTC发生发展中的重要作用。

MicroRNA(MiRNA)的异常表达在甲状腺乳头状癌（PTC）的发生发展中起重要调控作用。本项目探讨miR-151-5p、miR-20b和miR-195在PTC中的差异表达及其作用机制。我们研究发现miR-151-5p在PTC患者甲状腺癌组织中表达显著升高，且与淋巴结转移及肿瘤TNM分期相关，通过体外实验证实miR-151-5p增强PTC细胞的迁移和侵袭能力。随着我们对miRNA与PTC研究的深入，我们进一步揭示了miR-20b在PTC中的作用机制。研究结果发现miR-20b在PTC中呈低表达水平，且与肿瘤TNM分期相关，miR-20b在III/IV期中的表达水平明显低于I/II期。miR-20b通过作用于靶基因SOS1和ERK2，抑制MAPK通路的活性，从而抑制PTC细胞的增殖、转移和侵袭，促进细胞凋亡。此外，我们发现miR-195在PTC癌组织及细胞系中的表达水平显著降低。在K1和BCPAP细胞中高表达miR-195后，细胞的增殖、迁移和侵袭能力明显被抑制。CCND1和FGF2是miR-195的直接靶基因，而且在PTC组织中的表达水平与miR-195呈负相关。进一步研究显示miR-195可能通过抑制Wnt/β-catenin信号通路在PTC中起抑癌基因作用。该研究结果为甲状腺癌早期诊断及治疗提供新的理论基础。.5-羟甲基胞嘧啶（5hmC）异常表达发生在多种恶性肿瘤中，而催化5hmC生成的TET家族是引起5hmC表达变化的关键因素。我们发现PTC中5hmC低表达是由于TET1下调引起，5hmC可作为PTC发生的新的肿瘤标记物。TET1可以抑制PTC细胞迁移及侵袭，可能通过调控经典抑癌基因miR-7、miR-15/16家族、let-7家族和相关mRNA，参与Wnt/β-catenin信号通路发挥抑癌作用。该部分研究为进一步探索甲状腺癌的发生发展机制提供理论依据。