Takamura M, Sakamoto M, Genda T, Ichida T, Asakura H, Hirohashi S
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
Hepatology. 2001 Mar;33(3):577-81. doi: 10.1053/jhep.2001.22652.
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.
肝内转移是肝细胞癌（HCC）患者最重要的预后因素之一。最近研究表明，由Rho和p160 Rho相关卷曲螺旋形成蛋白激酶（p160ROCK）信号通路介导的细胞运动在人类HCC肝内转移中起关键作用。此外，将显性负性p160ROCK稳定导入Li7细胞可降低严重联合免疫缺陷（SCID）小鼠的转移率。为了研究特异性p160ROCK抑制剂Y-27632是否也能抑制肝内转移，研究了Y-27632对Li7细胞运动和肝内转移的影响。Y-27632显著阻断了溶血磷脂酸（LPA）介导的Li7细胞的肌动蛋白重组和运动。使用微渗透泵将Y-27632持续注入腹腔，同时将Li7细胞原位植入SCID小鼠肝脏。单独给予磷酸盐缓冲盐水（PBS）作为对照。Y-27632治疗组有转移结节的小鼠发生率降低。与对照组相比，Y-27632治疗组注射部位的原发肿瘤体积较小，但差异无统计学意义。组织学上，对照肿瘤在肿瘤边界处呈浸润性生长至窦状隙区域，而Y-27632治疗的肿瘤呈膨胀性生长且侵袭性低。这些发现证实了Rho/p160ROCK信号通路在人类HCC肝内转移中的重要性，并表明Y-27632可能有助于预防人类HCC的肝内转移。
