GRIP1基因在肝癌中的作用和分子机制研究

Hepatocellular carcinoma (HCC) is a malignant tumor prevalent in China. To now, the effect of treatment for HCC remains poor. The discovery of novel candidate genes related to HCC may help to clarify its pathogenesis and develop novel prevention, diagnosis and therapy strategies for HCC. Our previous whole exome sequencing identified GRIP1 as a candidate HCC gene, which was not reported to be involved in HCC. Our previous in vitro functional assays showed that GRIP1 could significantly suppress the proliferation of liver cancer cell lines. In addition, GRIP1 may act as a tumor suppressor by regulating p53 pathway. Furthermore, clinical analyses with small sample size showed that GRIP1 is significantly associated with the prognosis of HCC patients. However, there is no previous study on the biological function and molecular mechanisms of GRIP1 in tumorigenesis and development of HCC. Based on these results, we aim to confirm the tumorigenicity of GRIP1 by both in vitro and in vivo assays, and then determine the mechanisms, verify whether GRIP1 affects cell cycle or apoptosis by regulating p53 pathway, and ultimately affects cell proliferation. We will also evaluate the GRIP1 expression in HCC tissues and the correlation between GRIP1 expression or its mutations and prognosis of HCC patients. The aim of this study is to clarify the molecular mechanism of GRIP1 in the development of HCC, and our results may contribute to the future treatment of HCC.

肝癌是我国高发的恶性肿瘤，目前仍是临床上治疗效果最差的肿瘤之一。发现新的肝癌相关基因有助于解析其致病机制和研发新的防诊治措施。本实验室前期通过全外显子测序研究发现了新的肝癌候选基因GRIP1，目前，尚未有GRIP1在肝癌中发挥作用的报道。我们前期初步的功能研究显示，GRIP1基因能够显著抑制肝癌细胞系的生长；机制研究显示，GRIP1可能通过调控p53信号转导通路发挥抑癌作用；初步的临床相关性分析也显示GRIP1的低表达与肝癌患者较差的预后显著相关。本项目拟在前期研究基础上，通过体外和在体实验进一步确证该基因的致瘤性，并进一步探讨其分子机制，验证其是否通过调控p53信号通路影响细胞周期或凋亡，进而影响细胞的生长。我们还将评价其在肝癌组织中的异常表达情况，分析其突变或表达水平与肝癌病人预后的相关性。期望通过本项目阐明GRIP1在肝癌发生发展中的分子机理，为未来基于GRIP1的临床应用奠定基础。

肝癌是我国高发的恶性肿瘤，目前仍是临床上治疗效果最差的肿瘤之一。发现新的肝癌相关基因有助于解析其致病机制和研发新的防诊治措施。前期我们通过全外显子测序研究发现了新的肝癌候选基因GRIP1。目前，尚未有GRIP1在肝癌中发挥作用的报道。基于此，本项目拟在成瘤作用方面、分子机制方面和临床意义方面，对GRIP1开展系列研究。我们采用体外肝癌细胞和在体裸鼠皮下成瘤模型，敲低或过表达GRIP1，发现GRIP1在肝癌中发挥抑癌功能。进一步，我们发现GRIP1通过与14-3-3ζ相互作用，激活p53通路，进而抑制肝癌细胞的生长。我们还发现GRIP1在肝癌组织中显著低表达，且低表达与肝癌病人的较差临床预后相关。通过本项目，我们阐明了GRIP1在肝癌发生发展中的分子机理，为肝癌的防诊治措施提供了新的思路。