State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
Carcinogenesis. 2010 Sep;31(9):1676-84. doi: 10.1093/carcin/bgq134. Epub 2010 Jul 1.
Microtubule (MT) kinesin motor proteins orchestrate various cellular processes (e.g. mitosis, motility and organelle transportation) and have been implicated in human carcinogenesis. Kif18A, a plus-end directed MT depolymerase kinesin, regulates MT dynamics, chromosome congression and cell division. In this study, we report that Kif18A is overexpressed in human breast cancers and Kif18A overexpression is associated with tumor grade, metastasis and poor survival. Functional analyses reveal that ectopic overexpression of Kif18A results in cell multinucleation, whereas ablation of Kif18A expression significantly inhibits the proliferative capability of breast cancer cells in vitro and in vivo. Inhibition of Kif18A not only affects the critical mitotic function of Kif18A but also decreases cancer cell migration by stabilizing MTs at leading edges and ultimately induces anoikis of cells with inactivation of the phosphatidylinositol 3-kinase-Akt signaling pathway. Together, our results indicate that Kif18A is involved in human breast carcinogenesis and may serve as a potential therapeutic target for human breast cancer.
微管（MT）动力蛋白马达蛋白协调各种细胞过程（例如有丝分裂、运动和细胞器运输），并与人类致癌作用有关。Kif18A 是一种正向指向的 MT 解聚酶马达蛋白，可调节 MT 动力学、染色体汇聚和细胞分裂。在这项研究中，我们报告称 Kif18A 在人乳腺癌中过表达，并且 Kif18A 的过表达与肿瘤分级、转移和不良预后相关。功能分析表明，Kif18A 的异位过表达导致细胞多核化，而 Kif18A 表达的缺失显著抑制乳腺癌细胞在体外和体内的增殖能力。抑制 Kif18A 不仅影响 Kif18A 的关键有丝分裂功能，而且通过稳定 MT 在前沿，减少癌细胞迁移，最终导致细胞失巢凋亡，并使磷脂酰肌醇 3-激酶-Akt 信号通路失活。总之，我们的研究结果表明 Kif18A 参与了人类乳腺癌的发生，可能成为人类乳腺癌的潜在治疗靶点。
