14-3-3ζ 调控细胞自噬促进肝癌细胞向门静脉系统转移形成门静脉癌栓的分子机制研究

Mounting evidence suggests that hepatocellular carcinoma (HCC) metastasis through portal vein tumour thrombus (PVTT) is the key features for tumor metastasis in HCC patients. However, the mechanisms underlying initiation and progression of PVTT remain to be rescure. Our Previous study showed that 14-3-3ζ promotes promotes hepatocellular carcinoma venous metastasis by modulating hypoxia-inducible factor-1α under hypoxic conditions. Hypoxia induces autophagy is strongly correlated with the progression of tumor. More importantly, we found that the increased intratumoral hypoxia was strongly correlated with the autophagic activity in clinical samples. Therefore, we speculate whether .14-3-3ζ involved in hypoxia-induce autophagy to promotes hepatocellular carcinoma venous metastasis. As respected, we identified 14-3-3ζ promotes autophagy under hypoxic condition. In the further study, we will focus on the molecular mechanism underlying 14-3-3ζ-induces autophagy of HCC cells under hypoxic condition. We content that successful completion of this project will shed light into the novel mechanisms for PVTT of HCC initiation and progression and provide potential therapeutical targets for PVTT

门静脉癌栓(Portal vein tumour thrombus，PVTT）是肝细胞癌转移的主要特征。缺氧微环境与PVTT的形成密切相关。我们的既往研究发现，缺氧条件下，14-3-3ζ通过调控HIF-1α激活EMT通路促进PVTT形成。但此项研究仍不足以阐释缺氧微环境促进肝癌PVTT形成的分子机制；缺氧诱导的细胞自噬与肿瘤的进展密切相关；因而，我们推测缺氧诱导的细胞自噬是否与PVTT形成相关；前期研究在临床标本中检测到缺氧状态与自噬活性密切相关；体内实验发现抑制肝癌细胞自噬可以显著肝癌裸鼠的PVTT栓形成。研究提示，14-3-3ζ调控着缺氧诱导的细胞自噬；我们将进一步研究14-3-3ζ调控细胞自噬的分子机制及细胞自噬活性对肝癌PVTT形成和发展的影响。通过这些研究，使我们能明确14-3-3ζ在缺氧诱导的细胞自噬在肝癌PVTT形成过程中的作用机制，为肝癌PVTT的防治提供新策略。

我们既往研究表明，14‐3‐3ζ在肝癌组织中高表达，且在肝癌向门静脉系统转移形成门静脉癌栓过程中起着十分重要的作用。基于我们既往研究结果，我们本研究的主要内容为进一步探索14-3-3ζ是否可通过调控肝癌细胞自噬促进肝癌进程。我们首先发现肝癌组织中14-3-3ζ和Beclin1表达存在明显的正相关；缺氧环境下，高表达的14-3-3ζ通过与Beclin1S295磷酸化位点结合，抑制Beclin1的降解，进而诱导肝癌细胞的自噬；14-3-3ζ诱导的肝癌细胞自噬可以增强肝癌细胞对化疗药物顺铂的化疗抵抗性。本项目研究结果表明，14-3-3ζ在肝癌发生和发展过程中起着十分重要的作用，14-3-3ζ可望作为肝癌防治的分子靶点。