Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632

Hepatology. 2001 Mar;33(3):577-81. doi: 10.1053/jhep.2001.22652.

Abstract

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 coiledcoil forming protein kinase (p160ROCK) signaling pathways has recently been shown to play a critical role in intrahepatic metastasis in human HCC. Furthermore, the stable introduction of dominant-negative p160ROCK into Li7 cells resulted in a reduced metastatic rate in mice with severe combined immunodeficiency (SCID). 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 reorganization and motility of Li7 cells mediated by lysophosphatidic acid (LPA). 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. Phosphate-buffered saline (PBS) alone was administered as the control. The incidence of mice with metastatic nodules decreased in the Y-27632-treated group. The primary tumor volume at the site of injection was smaller in the Y-27632-treated group compared with the control group, but the difference was not statistically significant. Histologically, control tumors showed infiltrative growth into the sinusoidal area at the tumor boundary, whereas Y-27632-treated tumors showed expansive growth and low invasiveness. 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.

MeSH terms

  • Actins / drug effects
  • Actins / physiology
  • Amides / pharmacology*
  • Animals
  • Carcinoma, Hepatocellular / prevention & control*
  • Carcinoma, Hepatocellular / secondary*
  • Cell Movement / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Liver Neoplasms / prevention & control*
  • Liver Neoplasms / secondary*
  • Lysophospholipids / pharmacology
  • Male
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyridines / pharmacology*
  • Tumor Cells, Cultured
  • rho-Associated Kinases

Substances

  • Actins
  • Amides
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Lysophospholipids
  • Pyridines
  • Y 27632
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases