新型PLK4抑制剂YLT-11抗结直肠癌作用及机制研究

结直肠癌（CRC）发病率已跃居全球恶性肿瘤发病率第三位，临床上因缺乏有效的分子指标导致靶向治疗疗效有限。已知PLK4高表达于CRC病人并与预后不良密切相关，提示PLK4可作为CRC的潜在治疗靶点。但现有的PLK4抑制剂抗肿瘤机制研究仅停留在抑制中心粒复制层面，对于该靶点抗CRC转移机制尚不清晰。我们前期研究证实PLK4通过激活Wnt通路诱发肿瘤细胞发生上皮-间充质转化（EMT），进而促进了CRC转移。遂推测PLK4抑制剂不仅可以抑制CRC细胞增殖，还能抑制Wnt通路介导的EMT和肿瘤转移。课题前期得到高活性高选择性PLK4抑制剂YLT-11，抑制CRC细胞增殖的同时干扰EMT的发生，并抑制CRC细胞的侵袭迁移。本研究拟在前期基础上，进一步研究YLT-11体内抗增殖以及抗转移效果，同时应用YLT-11深入研究PLK4在CRC转移中的角色，为该靶点抑制剂应用于CRC治疗提供依据。

The incidence of colorectal cancer (CRC) ranks third in all kinds of cancers around the worldwide. Nowadays, the targeted therapy for CRC still can’t be achieved because of the lack of identifiable molecular indicator. Recent studies have shown elevated expression of PLK4 kinase in CRC was often observed in poor prognosis. Our previous study has also confirmed that the high expression of PLK4 kinase in colorectal carcinoma cells would boost its EMT and migration, indicating that PLK4 kinase may affect the CRC development by regulating EMT. Therefore, PLK4 may become a promising target for the treatment of CRC, but the mechanism involved in this process still need to be further determined. After our previous design synthesis and screening, we found a new compound YLT-11 which could inhibit effectively the activity of PLK4 kinase and proliferation of colorectal carcinoma cells, as well as prevent the metastasis by disturbing EMT. Base on the preliminary study, this study will further investigate the effect of YLT-11 on CRC metastasis, especially the signaling pathway associated with PLK4 kinase and EMT. This study will provide a basis for treatment of CRC.