Extracellular matrix remodeling may predominate over hepatocyte injury in hepatocellular carcinoma development.

It has been suggested that both extracellular matrix (ECM) remodeling and persistent hepatocyte injury play important roles in liver carcinogenesis process. It is, however, still controversial which factor plays a predominant role. The aim of the present study was to examine the role of each factor in the liver enzyme-altered preneoplastic lesions, focusing on the relationship between the hepatocyte injury and fibrosis extension. The effects of two similar herbal medicines (Sho-saiko-to and Saiko-keishi-to: TJ-9 and TJ-10, respectively) were elucidated on the hepatocyte injury, fibrosis and preneoplastic lesions development using a choline-deficient-L-amino acid-defined (CDAA) diet rat liver carcinogenesis model. TJ-9 prevented fibrosis and glutathione S-transferase placental form (GST-P)-positive preneoplastic lesion development without reducing the hepatocyte injury as indicated by the serum markers. TJ-10 significantly protected against the hepatocyte injury. However, it did not exert any inhibitory effect on fibrosis and the development of preneoplastic lesions. Our in vitro study revealed that TJ-9 markedly suppressed the hepatic stellate cell activation whereas TJ-10 did not. These results suggested that the ECM remodeling plays a more important role than the persistent hepatocyte injury in the liver enzyme-altered preneoplastic lesion development in the rat.