E2F1调控驱动蛋白KIF14表达及其在肿瘤抗紫杉醇药物中的作用机制研究

Resistance to anti-neoplastic agents is the major cause of therapy failure, leading to disease recurrence and metastasis. Transcription factor E2F1 regulates cell proliferation and apoptosis. Recent evidence showed that E2F1, which is highly expressed in advanced malignant cancer cells, drives cancer progression and chemoresistance. We and others found that E2F1 has an important role in tumor chemoresistance to microtubule inhibitors, such as taxol. However, the mechanisms by which E2F1 regualtes cancer cell chemosensitivity to taxol remain not clear. The latest evidence reveals that tumor-associated mitotic kinesin KIF14 is aberrantly high in many tumor cells and is associated with cancer cell chemoresistance against taxol. We have preliminary data in the lab demonstrating the regulation of KIF14 expression by E2F1, which may have influence in chemoresistance to microtubule inhibitor-taxol. In this study, we will investigate the transcriptional regulation of KIF14 by E2F1 and its effect on cancer cell microtubule inhibitor resistance. This will provide the theoretical basis for promoting clinically individualized medicine.

抗药性的产生将会引起肿瘤复发和转移，是肿瘤治疗失败的主要原因。转录因子E2F1调节细胞的增殖与凋亡。最近的研究表明，E2F1在恶性肿瘤细胞中高表达，在促进肿瘤的发展，特别是肿瘤抗药性中发挥重要作用。我们和其它实验室的研究结果显示，转录因子E2F1参与调控肿瘤细胞对微管抑制剂药物，如紫杉醇的抗药功能，然而E2F1调控肿瘤细胞对紫杉醇药物敏感性的关键靶基因仍不清楚。近年来研究发现，肿瘤相关有丝分裂驱动蛋白KIF14在多种肿瘤中高表达，与肿瘤发生发展以及肿瘤对微管抑制剂药物紫杉醇的抗药性密切相关。我们的预实验结果显示，转录因子E2F1调控细胞内驱动蛋白KIF14的表达，可能参与肿瘤对微管抑制剂紫杉醇的抗药作用。本课题将深入研究转录因子E2F1对KIF14基因的转录调控，及其对肿瘤细胞抗微管抑制剂药物的作用机制。这将为临床肿瘤更好的个体化治疗和精准医疗提供理论依据。

转录因子E2F1是细胞增殖和凋亡的关键调控因子。近年来研究发现，E2F1在恶性肿瘤细胞中高表达，在促进肿瘤的发展，特别是肿瘤抗药性中发挥重要作用。我们和其它实验室的研究结果显示，转录因子E2F1参与调控肿瘤细胞对微管抑制剂药物，如紫杉醇的抗药功能，然而E2F1调控肿瘤细胞对紫杉醇药物敏感性的关键靶基因仍不清楚。本项目中我们鉴定出肿瘤相关有丝分裂驱动蛋白KIF14是转录因子E2F1的一个新的靶基因；功能上E2F1通过调控KIF14的表达影响肿瘤细胞对紫杉醇药物的敏感性；从机制上我们明确了E2F1通过影响Kif14和SVIL在胞质分裂中小体的定位，导致细胞有丝分裂失常，非整倍体细胞形成。我们的研究将将为临床肿瘤更好的个体化治疗和精准医疗提供理论依据。