肝脏祖细胞是原发性肝癌的起源细胞之一。研究表明在TGF-β长期作用下肝脏祖细胞可发生恶性转化而形成肝癌。但其具体机制尚待深入研究。我们前期研究发现：CTGF和TGF-β均在肝硬化组织中高表达，且肝硬化组织中有肝脏祖细胞的激活。肝脏祖细胞存在TGF-β的自分泌，CTGF可在肝脏祖细胞中被外源性和自分泌的TGF-β诱导。因此，TGFβ-CTGF轴在肝脏祖细胞中持续激活并在肝硬化的进展中持续增强。基于TGFβ-CTGF轴在肝硬化与肝脏祖细胞的表达特点及前期报道CTGF在原发性肝癌进展中的促进效应推测TGFβ-CTGF轴促进肝脏祖细胞恶性转化。本项目将通过体内外研究方案明确TGFβ-CTGF轴在肝脏祖细胞生物学功能和恶性转化中的作用及分子机制，为肝癌发生的机制以及防治奠定理论基础并提供新的靶点和思路。

Primary liver cancer can originate from the malignant transformation of hepatic progenitor cells (HPCs). Previous investigations reported that the malignant transformation of HPCs occurred under long-term induction of transforming growth factor β (TGF-β). However，the precise mechanism of TGF-β induced transformation of HPCs remains largely elusive. Our previous studies found that HPCs were activated in the cirrhotic liver and secreted TGF-β and connective tissue growth factor (CTGF), both of which showed oncogenic roles in liver cancer. Besides, we found that TGF-β induced secretion of CTGF in HPCs. Moreover, TGF-β signaling was intracrine activated and contributed to autonomous secretion of CTGF in HPCs. These results suggested that the activated TGFβ-CTGF axis existed in HPCs and was elevated by TGF-β in the cirrhotic liver. Besides, from our previous studies we supposed that in the cirrhotic liver, the TGFβ-CTGF axis may contribute to the malignant transformation of HPCs. To confirm this hypothesis, we plan to carried out in vitro and in vivo experiments to investigate the role of TGFβ-CTGF axis in the proliferation, self-renewal and differention of HPCs. In addition, experiments for investigating the TGFβ-CTGF axis in the cell growth, self-renewal capacity, migration, epithelial-mesenchymal transition, chemoresistance, and tumorigenicity of TGFβ-transformed HPCs are also plan to perform. The downstream cascades of TGFβ-CTGF axis involving in the transformation of HPCs will be screened by antibody array and be verified by in vitro and in vivo functional experiments of HPCs. The results of purposed experiments will elucidate the precise role of TGFβ-CTGF axis in HPCs, and could help us finding a novel strategy for HCC prevention and therapy targeting hepatic tumor-initiating cells.