KIF3A基因过表达通过Wnt/β-catenin信号通路促进三阴性乳腺癌增殖及侵袭转移的机制研究

Triple negative breast cancer (TNBC) does not respond well to hormone and anti-Her-2 therapy and is associated with poor overall patient prognosis. Looking for a new target of anti-TNBC therapy has become the research hotspot. Wnt/β-catenin signaling pathway has critical roles in the development of tumor and particularly activated in TNBC. KIF3A, as a member of the kinesin family of motor proteins, promotes proliferation and invasion via Wnt signaling in prostate cancer. Our previous studies showed that the expression of KIF3A was higher in TNBC than that in the adjacent tissues,and its expression was positively correlated with lymphatic metastasis. Therefore we speculate KIF3A might regulate cell proliferation and invasion via Wnt/β-catenin signaling pathway in TNBC. In this study, RNAi and gene expression technique were used in both in vitro and in vivo experiments in order to observe the effects of KIF3A on the proliferation and invasion of MDA-AB-231, MDA-AB-468 and BT-20 cells. In addition, the mechanism of KIF3A regulating the proliferation and invasion of tumor cells were explored by analyzing the relationship between KIF3A and Wnt/β-catenin signaling pathway. Therefore this research will provide theoretical basis for seeking a new target of anti-TNBC therapy.

三阴性乳腺癌（TNBC）患者因不能从内分泌和抗Her-2治疗中受益而预后较差，寻找抗TNBC治疗的新型靶向分子成为研究热点。Wnt/β-catenin信号转导通路在肿瘤的发生发展中起关键作用，且在TNBC中存在异常激活。KIF3A是驱动蛋白家族成员，能通过激活Wnt信号通路促进前列腺癌的增殖和侵袭。我们前期研究发现，KIF3A在TNBC中过表达，并与淋巴结有无转移成正相关。由此推测，KIF3A通过Wnt/β-catenin信号通路调控TNBC的增殖和转移。本研究拟以MDA-AB-231，MDA-AB-468，BT-20细胞及裸鼠移植瘤为研究对象，采用基因干扰和过表达技术，从体内、体外两个层面探讨KIF3A对细胞增殖、侵袭的影响，同时通过研究KIF3A与Wnt/β-catenin信号通路的关系，探讨KIF3A调控细胞增殖、侵袭的分子机制。该研究将为抗TNBC治疗筛选新型靶分子提供理论依据。

三阴性乳腺癌（TNBC）患者因不能从内分泌和抗Her-2治疗中受益而预后较差，寻找抗TNBC治疗的新型靶向分子成为研究热点。Wnt/β-catenin信号转导通路在肿瘤的发生发展中起关键作用，且在TNBC中存在异常激活。KIF3A是驱动蛋白家族成员，能通过激活Wnt信号通路促进前列腺癌的增殖和侵袭。我们前期研究发现，KIF3A在TNBC中过表达，并与淋巴结有无转移成正相关。由此推测，KIF3A可能通过Wnt/β-catenin信号通路调控TNBC的增殖和转移。.我们的实验结果显示，KIF3A基因沉默抑制TNBC细胞MDA-MB-231及BT-549的增殖、侵袭及迁移能力，细胞形态变短，粘附性增强。而KIF3A过表达促进TNBC细胞BT-20的增殖及侵袭迁移，细胞形态变长，粘附性减弱。此外，KIF3A沉默可抑制细胞内Wnt/β-catenin信号通路相关分子β-catenin、CyclinD1、C-myc、Vimentin、MMP-2、MMP-9、DVL2及磷酸化DVL2的表达，而促进E-cad的表达。该结果同时被KIF3A过表达组实验结果验证。并且，酪蛋白激酶CK1抑制剂D4476可以逆转KIF3A过表达导致的β-catenin升高及DVL2的磷酸化。动物实验结果显示，KIF3A沉默组移植瘤生长较慢，瘤组织内β-catenin、CyclinD1、C-myc、DVL2及P-DVL2表达下调。KIF3A沉默组肺转移结节明显减少，瘤组织内Vimentin、MMP-2及MMP-9表达较弱，而E-cad的表达增强。由此我们推测：KIF3A基因沉默能抑制TNBC细胞的增殖、侵袭及转移能力，KIF3A基因过表达可能通过激活Wnt/β-catenin信号通路调控TNBC细胞的增殖和侵袭能力；并且这种激活作用可能是通过CK1依赖的DVL2磷酸化而实现的。KIF3A可能成为治疗人TNBC新靶点。