p62-mTORC1-自噬通路在肝癌发生发展中的作用及机制研究

The high frequency of intrahepatic recurrence and extrahepatic metastasis are still the major obstacles for long-term survival of hepatocellular carcinoma (HCC). Recent discoveries have pointed to deregulation of autophagy as a novel feature that is central to the pathogenesis of human malignancy. In eukaryotic cells, the mammalian target of rapamycin complex 1 (mTORC1) acts as a major regulator of autophagy. Autophagy inhibition could lead to p62 accumulation. Therefore, to clarify the molecular mechanisms of p62-mTORC1-autophagy pathway in tumorigenesis and progression of HCC has important clinical and theoretical significance. Our previous studies found that p62 expression was significantly upregulated in high invasive and metastatic potential of HCC cell lines, and knock-down p62 expression could inhibit cell proliferation and induce apoptosis, suggesting that p62 overexpression may be involved in the development of HCC. Therefore, we hypothesis that the abnormal p62-mTORC1-autophagy pathway promote HCC recurrence/metastasis. To verify this hypothesis, we used small animal optical in vivo imaging, real-time PCR, western blot, adenovirus vector transfection and RNA interference means to reveal the role of p62 in tumorigenesis and progression of HCC. We aimed to reveal the molecular mechanisms of p62-mTORC1-autophagy pathway in the progression of HCC. This study will focus on autophagy to reveal the tumorigenesis and progression of HCC. In the future, treatment targeted to clearance of p62 and block the related functions of p62 could be attractive therapeutic strategies against cancer prevention and treatment.

复发和转移是制约肝癌患者长期生存的关键因素。自噬功能失调是人类恶性肿瘤的新特征，mTORC1是调控自噬的关键分子，抑制自噬导致p62积聚。因此，阐明p62-mTORC1-自噬通路在肝癌发生发展中的分子机制具有重要的临床及理论意义。申请者前期研究发现p62在高侵袭转移潜能的肝癌细胞株中表达上调；敲减p62后细胞增殖减缓、凋亡增加，提示p62异常高表达可能与肝癌复发转移密切相关。据此提出假说p62-mTORC1-自噬通路调控异常促使肝癌进展。为验证该假说本项目采用小动物活体成像技术、RT-PCR、WB、腺病毒载体转染、RNA干扰等手段，从分子、细胞、组织以及动物水平等多层次阐明p62在肝癌发生发展中的作用，揭示p62-mTORC1-自噬通路参与肝癌发生发展的分子机制。本研究将从自噬这个新视点为揭示肝癌的发生发展机制奠定基础，为抗肿瘤治疗提供新思路，并为发展新型的分子药物提供干预靶点。