SIK1/PKM2/REGγ信号通路通过调控糖酵解抑制肝癌进展的分子机制研究

The glycolysis plays a critical role in the progression of hepatocellular carcinoma (HCC). Our previous studies have shown that SIK1 functions as a tumor suppressor in HCC initiation and development. However, how SIK1 affects glycolysis in HCC remains unclear. In the early study, we found that: (1) SIK1 oeverexpression inhibits glucose uptake, lactate production, and glycolysis in HCC cells; (2) Mass spectrometry and co-immunoprecipitation assays indicate that SIK1 might form a big complex with REGγ and PKM2; (3) There is a conserved phosphorylation motif in the protein sequence of PKM2. Given the important role of PKM2 in the glycolysis and REGγ’s ligase activity, we reasoned that the SIK1/PKM2/REGγ signal pathway and its circuit inhibits hepatocellular carcinoma development through regulating glycolysis. To this end, we used various molecular biological methods, cell lines, animal model, and clinical samples to elucidate the mechanism. Therefore, this study may shed novel light into the regulation mechanism of HCC glycolysis and represent a new therapeutic target for inhibiting HCC.

糖酵解在肝细胞癌的发生发展中起着重要的作用。我们前期研究证实SIK1为肝细胞癌的肿瘤抑制因子，然而其如何通过糖酵解调控肝细胞癌的进展仍不明确。通过预实验我们发现：（1）过表达SIK1能够抑制肝细胞癌细胞的糖原消耗、乳酸产生及糖酵解效率；（2）通过质谱分析及免疫共沉淀发现SIK1能与REGγ及PKM2蛋白相结合；（3）通过分析PKM2蛋白序列发现其存在SIK1的保守磷酸化序列，基于PKM2在糖酵解中的作用及REGγ的泛素化特性，我们推测：SIK1/PKM2/REGγ通路及自身环路通过调控糖酵解抑制肝细胞癌的发生发展。本课题拟用多种生物学研究方法，在细胞水平、分子机制水平、动物水平和临床水平阐述SIK1/PKM2/REGγ这一通路调控肝细胞癌糖酵解及进展的机制，本研究有望为肝细胞癌的靶向治疗提供新依据。