Molecular mechanisms of intrahepatic metastasis of hepatocellular carcinoma and application for diagnosis and treatment

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Intrahepatic metastasis is one of the most important prognostic factors for patients with hepatocellular carcinoma (HCC). Cell motility mediated by Rho-and p160 Rho-associated coiled-coil forming protein kinase (p160ROCK) signaling pathways has recently been shown to play a critical role in intrahepatic metastasis in human HCC. One of such highly metastatic cell line, KYN-2 cells having a high level of c-Src kinase activity become scattered, extend lamellipodia, and exhibit high motility in adherent condition. Expression of a dominant-negative mutant form of c-Src caused formation of stress fibers and focal adhesions, and markedly reduced motility. it was suggested that c-Src activation is critically involved in carcinoma cell migration and metastasis. To investigate whether the specific p160ROCK inhibitor Y-27632 could also inhibit intrahepatic metastasis, the effect of Y-27632 on the cell motility and intrahepatic metastasis of Li7 was investigated. Y-27632 markedly blocked actin reo … More rganization and motility of Li7 cells mediated by lysophosphatidic acid. Y-27632 was administered continuously into the peritoneal cavity using a micro-osmotic pump, together with orthotopic implantation of Li7 cells into the liver of SCID mice. The incidence of mice with metastatic nodules decreased in the Y-27632-treated group. These findings confirm the importance of the Rho/p160ROCK signaling pathway in intrahepatic metastasis of human HCC, and indicate that Y-27632 may be useful for the prevention of intrahepatic metastasis of human HCC.Crucial genes involved in liver cancer metastasis were screened using differential display analysis. A novel gene, DRH1, which is frequently down-regulated in HCC was identified. CO-029 was found to be frequently and significantly overexpressed in HCC and in tumors with intrahepatic spreading. In contrast, mRNA expression of the other tetraspanins CD9 and CD82 was down-regulated in HCC, especially in tumors with intrahepatic spreading. It was suggested that CO-029 has some roles in the promotion of metastasis of HCC. Less