肝硬化所致的细胞外基质高硬度微环境是导致肝细胞癌（HCC）发生发展的关键因素，但具体机制目前仍很不清楚。我们已发表成果证实肝星状细胞（HSCs）在肝脏肿瘤微环境中发挥重要作用（Hepatology,2015）。我们前期发现①高基质硬度诱导HSCs活化并分泌COMP蛋白，P300在此过程中发挥关键调控作用；②血清COMP高表达提示HCC患者预后不良；③重组人COMP激活PI3K/AKT和MEK/ERK通路并促进HCC细胞生长和侵袭转移。因此，我们拟通过临床和功能学实验证实如下科学假说：细胞外基质高硬度微环境中P300与RhoA形成正反馈环路促进HSCs活化并分泌COMP蛋白，HSCs源性COMP与膜受体CD36结合并激活PI3K/AKT和MEK/ERK通路，从而促进HCC细胞生长和侵袭转移。同时，本项目拟研究特异性COMP单抗在动物体内抗HCC作用，为临床上开发新HCC靶向治疗药物提供依据。

Extracellular matrix stiffness-related microenvironment, resulted from liver cirrhosis, is the main reason for the initiation and progression of hepatocellular carcinoma (HCC). However, the underlying mechanisms remain largely unknown. Our published data proved that hepatic stellate cells (HSCs) play an important role in the liver tumor microenvironment (Hepatology, 2015). Our previous studies found that matrix stiffness induced HSCs activation and COMP secretion, and P300 exerted an critical regulatory role in this process. High level of serum COMP indicated a poor prognosis of HCC patients. In addition, recombinant human COMP promoted the activation of PI3K/AKT and MEK/ERK pathways, and facilitated HCC cell growth and metastasis. Thus, clinical and biological experiments will be performed to verify the following scientific hypothesis that P300-RhoA positive feedback loop maintains HSCs activation and promotes COMP secretion in extracellular matrix stiffness-related microenvironment. HSCs-sourced COMP binds to membrane receptor CD36 and activates PI3K/AKT and MEK/ERK pathways, and subsequently promotes HCC cell growth and metastasis. Furthermore, high level of serum COMP is an independent prognostic factor for predicting poor prognosis of HCC patients. Meanwhile, the anti-HCC effect of the specific COMP monoclonal antibody will be investigated in a mouse model. Altogether, our project is aimed to provide the basis for the development of new HCC targeted therapy drugs.