MiR-613在乳头状甲状腺癌侵袭转移中的作用及机制的研究

Papillary thyroid carcinoma (PTC) arising from normal follicular cells is the most frequent carcinoma of the thyroid and is generally associated with slow growth and good prognosis.However, some cases show relatively early recurrence, severe invasion, multiple lymph node metastasis,or distant metastasis.it is essential to investigate the molecular mechanism of the PTCs that have a high risk for invasion and metastasis for improving their therapy and survival..Our preliminary studies showed miR-613 may mediate interaction of extracellular matrix receptors and suppress invasion and metastasis of PTC by microRNA and cDNA expression microarray analysis between aggressive and nonaggressive PTC tissues. To validate this preliminary results, we will further investigate the mechanism of which miR-613 regulates invasion and metastasis of PTC by two PTC cell lines with the methods of gene overexpression and silence,orthotopical xenografted mouse model,loss-of-function and epistasis experiments, antibody neutralization and image and so on in many ways of molecule, cell, animal and clinical tissue samples in this project..We will identify a novel miRNA which supresses invasion and metastasis of PTC, and elucidate FN1 and CD44,IGTA2,IGTA8 extracellular matrix receptors interaction pathways as regulators of invasion and metastasis of PTC, which will estabilish fundation for target of therapy in invasion and metastasis of PTC, and provide some clues for searching markers of early warning in invasion and metastasis of PTC.

近年来，乳头状甲状腺癌（PTC）发生率呈逐年增长趋势，部分PTC具有明显侵袭转移潜能。最近的研究提示某些microRNAs为PTC侵袭提供线索。我们项目组前期应用microRNA与基因表达谱芯片联合分析显示：miR-613可能负调节靶基因FN1抑制PTC侵袭转移，且可能与CD44、ITGA2、ITGA8细胞外基质受体有关。在此基础上，本项目拟进一步通过两个PTC 细胞株，采用基因过表达与沉默、原位移植转移模型、功能缺失与上位实验、抗体阻断及影像等手段，从分子、细胞、动物、临床组织等多方面验证miR-613依赖于靶基因FN1与CD44、ITGA2、ITGA8细胞外基质受体途径而抑制PTC细胞的侵袭转移。本项目将识别内源性抑制PTC侵袭转移的新microRNA，阐明PTC侵袭转移的miR-613/FN1/CD44、IGTA2、IGTA8调节途径，对PTC侵袭转移的靶向性治疗提供理论与实验依据。

近年来，乳头状甲状腺癌肿瘤的发病率逐年上升，已经成为内分泌系统肿瘤中的最常见肿瘤。其中部分乳头状甲状腺癌具有明显的侵袭转移潜能。2012年我们项目组前期应用组织标本的microRNA表达谱芯片分析显示：miR-613与乳头状甲状腺癌的侵袭转移相关，但miR-613在甲状腺癌中的功能以及在乳头状甲状腺癌中的侵袭转移机制未见报道。.在本课题的研究期间的主要创新点为首次发现和揭示了：1）miR-613可以抑制乳头状甲状腺癌的侵袭与迁移；2）SphK2在乳头状甲状腺癌中高表达，并可促进乳头状甲状腺癌的侵袭与转移；3）miR-613主要通过靶向抑制SphK2基因的表达来抑制乳头状甲状腺癌的细胞功能；4）ZNRF3基因在乳头状甲状腺癌中低表达，并可抑制乳头状甲状腺癌细胞的恶性表现；5）WNT信号通路相关蛋白b-catenin/TCF4在乳头状甲状腺癌中高表达，并与甲状腺癌的临床表型密切相关；6）ZNRF3可通过抑制WNT信号通路来抑制甲状腺癌的恶性转化；7）miR-613及ZNRF3基因有望成为治疗早期转移的乳头状甲状腺癌的新靶点。