PLK5/VHL/HIF1a信号通路促进肝细胞癌发生、发展的分子机制研究

肝细胞癌(HCC)是我国死亡率最高的癌症之一。鉴于现有分子靶向药物种类的匮乏及其在HCC治疗领域的独特优势，深入探索HCC发病的分子机制、寻找新靶点尤显重要；我们前期实验发现 (1)PLK5在HCC肿瘤组织中高表达且与HCC恶性程度呈正相关；(2)PLK5可与VHL直接结合并磷酸化VHL，使其丧失降解HIF1α的能力，导致HIF1α因降解减少而在胞质中蓄积、入核激活HIF1α及系列信号通路；(3)PLK5启动子上有HIF1a可识别的保守序列，高表达的HIF1α诱导PLK5高表达；(4)动物水平上过表达的PLK5可促进HCC的增殖和远处转移。. 据此，我们提出PLK5/VHL/HIF1α可共同形成正反馈环路、促进HCC增殖、侵袭及转移的假说，将借助多种生物技术从分子、细胞、动物和临床多层面阐述该反馈环路促进HCC发生发展的机制，有望为HCC的精准治疗提供潜在治疗靶点。

Hepatocellular carcinoma (HCC) is one of the cancers with the highest mortality in China. Given the lack of existing molecular targeted therapeutic drugs and having huge advantages over traditional treatments in cancer, Molecular targeted therapies are eager for more details about the mechanisms of HCC. Our previous experiments found that: (1) The relative expression of PLK5 is significantly elevated in HCC tissues and cells, which is positively correlated with the malignant degree of HCC; (2) PLK5 can directly bind to VHL and phosphorylate VHL. Phosphorylated VHL are disabled to degrade HIF1a that accumulated in cytoplasm, resulting in the activation of the HIF1a signal pathway by the way of HIF1a shuttling into nucleus; (3) The conservative sites recognized by HIF1a exist in the PLK5 promoter and overexpression of HIF1a induces the elevation of PLK5; (4) The overexpression of PLK5 in BALB/c nude mouse promotes the proliferation and distant metastasis of HCC. . Based on the findings, not only does PLK5 upregulate the level of HIF1a, HIF1a transactivates the promoter of PLK5, suggesting a positive feedback loop. Therefore, we speculate that PLK5/VHL/HIF1a signal pathway plays a critical role in occurrence, progression, proliferation, invasiveness and metastasis of HCC. By using a variety of multiple molecular biology tools, cell culture and mice models , we desperately want to investigate the role of PLK5/VHL/HIF1a signal loop in HCC. Our upcoming research is expected to make us learn more about HCC and to provide potential therapeutic targets for the treatment of HCC.