人驱动蛋白KIF14在结、直肠癌发生中的作用及其分子机制

Colorectal cancer(CRC) is one of the leading cause of death from malignancies in the World. Treatment of CRC has been virtually unchanged in over 40 years and includes surgery and chemotherapy. Improved surgical techniques, new chemotherapeutic agents, altered modes of chemotherapy delivery and emerging molecular targets have improved life expectancy but have done little to impact cure rates. There is a desperate need for improved early detection, diagnostic and prognostic indicators, and the identification of molecular pathways that drive and maintain CRC cells, to achieve novel therapies that can cure.High KIF14 expression in colorectal cancer could suggest that the oncogenic role of KIF14 has wide relevance to cancer. Human KIF14 was first identified as a 6,586 base-pair kinesin family 10 cDNA clone. Like all kinesins, KIF14 is a microtubule-dependent molecular motor, containing a kinesin motor domain and a forkhead- associated domain. KIF14 also contains an C-terminal citron kinase (CIT) binding region and a N-terminal protein regulating cytokinesis (PRC1) binding region.KIF14 function has been only partially characterized, showing that it is essential for the final phase of cytokinesis,where interaction with PRC1 and CIT is required. Knockdown of KIF14 in HeLa cells results in the generation of binucleate cells, polyploidy and apoptosis, depending on the degree of knockdown. Reports showed that transient KIF14 knockdown by siRNA in H1299 and HeLa cells significantly decreased proliferation and colony formation, suggesting that KIF14 may have an important oncogenic role in cancer cells.

人体内的驱动蛋白Kinesin家族成员与结、直肠癌的发生、发展有着密切的关系，其中Eg5、CENP-E的多种抑制剂、抗体已经进入某些肿瘤治疗的I期或II期临床试验，并且已有明显的临床效果。人驱动蛋白KIF14(Kinesin-3)表达水平的升高与多种肿瘤的发生、转移以及对药物的敏感性有关。研究表明，KIF14可通过促进AKT磷酸化从而促进癌细胞的增殖水平，通过RNAi的方式下调KIF14的水平，可以促进癌细胞凋亡，并减小裸鼠内肿瘤的大小。KIF14亦可通过促进AKT磷酸化从而参与癌症的发生。抑制KIF14的表达可以降低AKT的磷酸化，并提高癌细胞对化疗药物的敏感性。前期结果显示KIF14在结直肠癌患者肿瘤组织中异常升高，进一步的研究主要集中在KIF14下游信号转导机制的研究，其分子机制为KIF14作为新的治疗靶标，为结直肠癌的临床治疗提供新的线索和理论依据。

人体的驱动蛋白Kinesin家族成员与细胞增殖、肿瘤的发生、发展有着密切的关系，其中多种Kinesin分子的小分子抑制剂、抗体已经进入某些肿瘤治疗的I期或II期临床试验，并且已有明显的临床效果。人驱动蛋白KIF14(Kinesin-3)表达异常与多种肿瘤的发生、转移以及对药物的敏感性有关。我们的研究表明，KIF14在结直肠癌患者肿瘤组织中异常升高，KIF14可通过促进AKT磷酸化，通过RNAi的方式下调KIF14的水平，可以抑制AKT磷酸化的水平及下游信号分子的激活。pAKT下游HIF-1a可以抑制结肠上皮细胞中的Wnt信号的激活，显著降低β-catenin、DKK1的胞内水平，显著增加了p-eIF2的水平。内质网应激可能是pAKT/HIF-1a/Wnt信号通路cross-talk的交汇点。这些结果为结直肠癌的临床治疗提供新的线索和理论依据。