AKR1C3对肝癌细胞增殖和转移的调控及其分子机制研究

代谢重编程在肿瘤发生发展的过程中发挥关键作用，针对关键代谢酶调控的研究可以从新的角度去阐释肿瘤发生发展的机制。AKR1C3是体内类固醇激素代谢的关键酶，其表达异常与肿瘤发生发展的关系密切，但其在肝癌中表达调控机制缺乏深入的研究。我们前期发现AZGP1抑制肝癌细胞增殖和转移，AZGP1抑制AKR1C3的表达，提示AZGP1可能参与对AKR1C3表达的调控；AKR1C3在肝癌组织中表达增高，并能促进肝癌细胞增殖、迁移和侵袭，提示AKR1C3与肝癌细胞增殖和转移密切相关；过表达AKR1C3可激活肝癌细胞NF-κB信号通路，并且氧化应激可上调肝癌细胞AKR1C3的表达，但其具体分子机制不清。本课题拟采用细胞、动物模型及临床肝癌组织样品等体系，深入研究AKR1C3在肝癌细胞增殖和转移中的作用及其分子调控机制。通过阐明AKR1C3在肝癌中的表达调控机制，为探索肝癌发生发展的机制及治疗策略提供新的思路。

Metabolic reprogramming plays a key role in tumorigenesis and development. The study on the regulation of the key metabolic enzymes could provide a new perspective to explain the mechanism of tumorigenesis and development. AKR1C3 is a key enzyme in the regulation of steroid hormone metabolism, which is closely related with development and progression of tumors. But the expression and regulatory mechanisms of AKR1C3 in hepatocellular carcinoma (HCC) still lack a deep research. Our previous study showed that AZGP1 inhibited the proliferation and metastasis of HCC. AZGP1 inhibited expression of AKR1C3 in HCC cells. It means that AZGP1 may be involved in the regulation of AKR1C3 gene expression in HCC. The expression of AKR1C3 was up-regulated in human HCC tissues compared with non-cancerous liver tissues. In vitro experiments showed that AKR1C3 promoted the proliferation, migration and invasion of HCC cells. These results suggest that AKR1C3 may be closely related with the cell proliferation and metastasis of HCC. We found that NF-κB signaling pathway was activated in AKR1C3 overexpressing HCC cells. Moreover, the expression of AKR1C3 was increased under oxidative stress in HCC cells. However, these specific molecular mechanisms linking the AKR1C3 are unclear. We will clarify the role of AKR1C3 in HCC proliferation and metastasis and its molecular mechanisms using cell lines, animal models and HCC tissue in vitro and in vivo. The results not only illustrate the regulatory mechanism of AKR1C3 expression in development and progression of HCC, but also provide new ideas on the pathogenesis and therapeutic targets of HCC.