IQGAP1促进甲状腺癌侵袭转移的作用及机制研究

Our previous NSFC project (30600601) demonstrated that IQGAP1 has close association with oncogene PPFP. Futher studies showed that increase of IQGAP1 was more obvious in metastasis compared with tumor tissues and has a negative correlation with miR-124 expression. All these results suggested that IQGAP1 has a close relationship with thyrod tumor invasion and metastasis. However, the details of action mechanism remains unclear. Firstly, the project will systematically analyse how the alteration of IQGAP1 expression affects the biological behavior of thyroid cancer especially invasion and metastasis. Secondly, the effect of miR-124 overexpression on IQGAP1 and the invasion and metastasis of thyroid cancer will be studied and IQGAP1 as the target gene of miR-124 will be validated. Therefore, the role of miR-124 in invasion and metastasis of thyroid cancer will be demonstrated. Lastly,technologies of tandem affinity purification(TAP) and targeted proteomics will be used to isolate and identificate the interacting protein of IQGAP1, and to explore the network characteristics of these protein interaction; addtionally, IQGAP1 functions via related signalling pathway will be comfirmed. All the studies will provide new clues to prevention and treatment of the invaison and metastasis of thyroid cancer.

我们以前的国基课题（30600601）发现IQGAP1与甲状腺癌相关癌基因PPFP密切相关，进一步研究发现IQGAP1的表达增加在甲状腺癌转移灶中更为明显，且与miR-124表达与呈负相关。以上结果提示IQGAP1与甲状腺癌的侵袭转移密切相关，但究竟是通过何种机制促进甲状腺癌转移仍不明确。本项目拟在此研究基础上首先系统分析IQGAP1的表达水平改变对甲状腺癌侵袭转移的影响，阐明IQGAP1在甲状腺癌转移中扮演的角色；其次，通过改变miR-124在甲状腺癌细胞中的表达水平研究其对IQGAP1的调控作用及机制，进一步阐明miR-124在IQGAP1促进侵袭转移中的作用。最后，通过以串联亲和纯化耦联质谱技术为主的靶向蛋白质组学技术分离、鉴定甲状腺癌细胞中IQGAP1蛋白的相互作用蛋白，确定IQGAP1通过相关信号传导通路促进甲状腺癌侵袭转移的分子机理，为甲状腺癌转移的断治研究提供新线索。

本项目在上一个课题的研究基础上首先检测IQGAP1在甲状腺癌组织中的表达情况，阐明IQGAP1在甲状腺癌侵袭转移的作用。其次筛选在甲状腺癌组织中低表达的microRNA，并进一步筛选出与IQGAP1相互作用的miRNA。最后鉴定甲状腺癌细胞中IQGAP1参与的相关信号传导通路促进甲状腺癌侵袭转移的分子机理。本研究发现IQGAP1在甲状腺癌组织，癌细胞中高表达。IQGAP1沉默后肿瘤细胞增殖，侵袭转移明显受到抑制。通过microRNA芯片，我们筛选到多个低表达miRNA，并证实miR-124直接作用与IQGAP1 3’UTR序列，起负性调节IQGAP1表达的作用。并进一步证实miR-124在IQGAP1促进肿瘤增殖，侵袭转移中发挥重要调控作用。通过生物信息学分析，我们发现高表达IQGAP1可能通过多条信号通路参与甲状腺癌发生发展，并证实IQGAP1参与JAK/STAT信号通路活化。本研究阐明了IQGAP1在甲状腺癌转移中扮演的重要角色，证实IQGAP1高表达由miRNA参与介导的调节机制，并证实IQGAP1参与的肿瘤相关信号通路。本研究为甲状腺癌转移的诊断治疗研究提供新线索。