Rab42通过PI3K/Akt信号通路调控肝癌生长转移的作用及机制研究

As a molecular switch for intracellular vesicle transport, Rab protein plays an important role in different stages of vesicle transport. Altered expression or mutation of Rab protein can lead to vesicle transport disorder, which not only affects cell secretion, endocytosis and signal transduction, but also affects tumor cell proliferation, apoptosis, differentiation and metastasis. Rab42 is a recently detected protein of the Rab family, and its function and relation to tumor development have not been investigated yet. Our previous studies found that increased expression of Rab42 significantly promoted the proliferation and invasion of hepatocellular carcinoma (HCC), and HCC cells with different Rab42 expression demonstrated differentially expressed genes. Further KEGG pathway enrichment analysis revealed that PI3K/Akt signal pathway was significantly affected. Therefore, we speculate that Rab42 may regulate the growth and metastasis of HCC via the PI3K/Akt signaling pathway. In this study, we want to confirm the above hypothesis and clarify the definite mechanism of Rab42 in regulating the growth and metastasis of HCC. In addition, we also want to explore the feasibility of Rab42 as a prognostic factor and potential therapeutic target for HCC. These studies will contribute to the understanding of Rab protein family in regulating tumors, provide new ideas to target treatment for HCC, and thereby help to improve the prognosis of HCC patients.

Rab蛋白作为细胞内囊泡运输的分子开关，在囊泡运输的不同阶段发挥重要作用。Rab蛋白表达改变或发生突变，会导致囊泡运输障碍，不仅影响细胞的分泌、胞吞及信号转导，还影响肿瘤细胞增殖、凋亡、分化与转移。Rab42是Rab家族新发现的一个蛋白，其功能及在肿瘤发生发展中的作用目前国内外并无相关研究。我们前期研究发现Rab42表达增加会促进肝癌的增殖和侵袭，并通过对不同Rab42表达水平肝癌细胞的差异表达基因进行KEGG富集分析，初步发现以PI3K/Akt为主的信号通路的改变。我们推测Rab42可能通过PI3K/Akt信号通路来调控肝癌的生长转移。本项目欲进一步证实上述假说，明确Rab42调控肝癌生长转移的具体作用机制，并探讨Rab42作为肝癌转移复发的分子预测标记和治疗靶点的可行性，以完善Rab蛋白家族对肿瘤调控作用机制的理解，为预测肝癌复发转移和靶向治疗提供新的思路，以进一步提高肝癌病人的预后

作为肝癌大国，我国肝癌的防治形势依旧严峻。全面深入研究调控肝癌发生发展的基因及相关信号通路，有助于寻找肝癌新的治疗靶点及分子预测标记，从而最大限度地抑制肝癌进展，改善肝癌患者预后。我们的研究明确了Rab42在肝癌组织中的表达变化，阐明了Rab42对肝癌细胞生物学功能的影响；同时分析Rab42蛋白水平在肝癌组织中的表达变化及其与肝癌患者预后的关系。我们还阐明了内源性大麻素2-AG及其合成酶DAGLA在促进肝癌进展、诱导索拉非尼耐药中的作用。我们发现DAGLA及2-AG在肝癌组织中呈高表达状态，高表达者生存时间较低表达者显著缩短。进一步研究发现，DAGLA/2-AG轴可促进肝癌的增殖、克隆形成、迁移及侵袭，并介导索拉非尼耐药。机制研究表明，DAGLA/2-AG轴能抑制LATS1磷酸化，抑制YAP磷酸化并促进其核转位，该过程可被激活的PI3K/AKT通路强化。YAP入核后与TEAD2组成转录因子复合体，结合PHLDA2启动子，促进PHLDA2的转录表达，诱导肝癌EMT发生，调控p57表达水平，最终促进肝癌进展。