肝细胞性肝癌（hepatocellular carcinoma，HCC）细胞的快速生长与HCC的不良预后密切相关，因此，探讨调控HCC细胞生长的分子机制具有重要意义。近年来，有关自噬相关蛋白4B（autophagy related 4B，ATG4B）调控肿瘤细胞生长的功能倍受关注，但其是否参与调控HCC细胞的生长，目前未见报道。我们在前期首次发现“ATG4B以自噬非依赖的方式促进HCC细胞生长，并对相关机制进行探索且有进一步创新发现”的基础上，提出如下假设：ATG4B可能通过介导“ATG4B-Akt”正反馈环路的形成而促进HCC细胞的生长。本项目将重点解析“ATG4B-Akt”正反馈环路形成的分子机制，证实ATG4B是Akt的一个新靶蛋白，揭示ATG4B的Ser34位点磷酸化在该正反馈环路形成中的关键作用，进而在HCC细胞模型、荷瘤鼠模型和临床HCC样本上探讨该正反馈环路促进HCC细胞生长的作用，为探索以ATG4B及其所介导的“ATG4B-Akt”正反馈环路为靶标的抗HCC新策略提供科学依据。

Rapid growth of hepatocellular carcinoma (HCC) cells is closely related to the poor prognosis of HCC. So it is significant to explore the regulation mechanisms of HCC cell growth. Recently, the function of autophagy related 4B (ATG4B）on the regulation of cancer cell growth has been received much concern. However, it is unclear whether ATG4B is involved in the regulation of HCC cell growth. Our preliminary data for the first time showed that ATG4B promotes the growth of HCC cells in an autophagy-independent manner, and furthermore, we did pilot investigation on the corresponding mechanism and got several novel findings. Based on the innovative discoveries, together with previous reports, we hypothesize that ATG4B may promote the growth of HCC cells via inducing the formation of the positive feedback loop of ATG4B/Akt. In the present project, we will mainly illustrate the detailed mechanism by which the positive feedback loop of ATG4B/Akt forms. Moreover, we will identify that ATG4B is a novel target protein of Akt, and clarify the significance of ATG4B phosphorylation at Ser34 site in the formation of the positive feedback loop. Subsequently, the HCC cells, HCC-bearing nude mice and clinical human HCC samples will be used to evaluate the importance of the feedback loop in promoting HCC cell growth. The expected results of this project may provide scientific evidences for exploring novel anti-HCC strategies targeted ATG4B and its mediated ATG4B/Akt positive feedback loop.