Rab27A/B基因异常对肝癌细胞恶性生物学行为的影响及其分子机制

The protein of both Rab27a and Rab27b genes are Ras families small molecules of GTP enzymes, which responsible for vesicle traffic within cell.It is confirmed Rab27a/b protein play an important in breast cancer development in previous reports. We also have found that almost 50% of hepatocellular cancer tissues over-express Rab27a, by contrast, almost 50% of hepatocellular cancer have low or no expression of Rab27b. Morover, the alteration of Rab27a/b is contribue to prognosis of hepatocellular in our previous tissues array study. In order to further elucidate the role of Rab27a/b genes playing in development of hepatocellular cacinoma, we shill establish high or low expression of Rab27a/b cell model, and observed changs of malignant bio-behavour,abilities of formal tumor or invasion and metastasis in vivo and in vitro in hepaocellular cancer cells by increase or knocking down expression of Rab27a/b genes. The research would further explain oncogene-like effect of Rab27a and tumor-suppression like effect of Rab27b,and supply an experimental support for Rab27a/b as a pronogic factor, for Rab27a/b as a molecular treatment target in hepatocelular carcinoma.

Rab27a和Rab27b蛋白是RAS家族小分子GTP酶，负责微小囊泡的运输，在乳腺癌的进展中发挥重要作用；我们在前期组织芯片研究中发现：近50%的肝癌高表达Rab27a，50%低表达Rab27b蛋白。为进一步阐明Rab27蛋白在肝癌发生发展中的作用，本项目通过建立Rab27蛋白高和低表达细胞模型，并通过转基因敲低或增加二基因的表达，来观察肝癌细胞恶性生物学行为改变，体内外成瘤能力和侵袭转移能力及其分子机制；以进一步明确Rab27a的癌基因样作用和Rab27b的抑癌基因样作用，为两基因蛋白作为肝癌预后指标奠定理论和实验基础，为肝癌的治疗提供新的靶标。

Rab27A是Rab小GTP酶家族成员，主要参与微小囊泡的胞内运输和分泌，在多种类型肿瘤的进展中发挥重要作用。我们在前期研究中发现：Rab27A在肝癌组织中高表达，且其高表达与不良临床病理学特征和预后差密切相关。在本研究中，为进一步阐明Rab27A在肝癌中的作用，我们检测了过表达/干扰Rab27A对肝癌细胞恶性生物学行为的影响，并通过mRNA及miRNA表达谱分析初步筛选Rab27A下游关键调控分子和信号通路。研究结果显示Rab27A表达水平与肝癌细胞体外增殖，迁移和侵袭能力呈正相关，进一步研究表明NF-kappa B信号通路，MAPK信号通路，趋化因子信号通路，toll-like receptor信号通路和PI3K-Akt信号通路可能参与了Rab27A对肝癌细胞的调控过程。并且，hsa-miR-514a-3p，hsa-miR-509-5p，hsa-miR-509-3-5p和hsa-miR-200b-3p有可能与Rab27A形成负反馈调节，共同参与调控肝癌细胞的恶性生物学行为。这一结果进一步明确了Rab27A在肝癌中的癌基因样作用，为疾病的临床诊断和治疗提供了理论基础和潜在靶点。