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Basic experiments of liver transplantation for hepatocellular carcinoma : Prevention of tumor recurrence using molecular target therapy

肝细胞癌肝移植基础实验：分子靶向治疗预防肿瘤复发

基本信息

批准号：
16591321
负责人：
TASHIRO Hirotaka
金额：
$ 2.24万
依托单位：
Hiroshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591321/
关键词：
rat hepatocellular carcinoma metastasis tacrolimus ROCK inhibitor migration ラット肝移植

项目摘要

Tumor recurrence after liver transplantation still remains a significant problem in patients with hepatocellular carcinoma. The small GTPase Rho/Rho-associated kinase (ROCK) pathway is involved in the motility and invasiveness of cancer cells. We investigated whether tacrolimus activated the Rho/ROCK signal pathway to promote the invasiveness of rat hepatocellular carcinoma cells. We also investigated whether the ROCK inhibitor Y-27632 suppressed tumor recurrence after experimental liver transplantation in a rat hepatocellular carcinoma model. Orthotopic liver transplantation was performed in hepatocellular carcinoma cell line McA-RH7777-bearing rats. Tacrolimus was administered to liver transplant rats and these rats were divided into two groups: the Y-27632-treated (10mg/kg, for 28 days) group and the Y-27632-untreated group. Tacrolimus enhanced the cancer cell migration and stimulated phosphorylation of the myosin light chain (MLC), a downstream effector of Rho/ROCK signaling. Y-27632 suppressed the cancer cell migration and tacrolimus-induced MLC phosphorylation. Suppression of tumor recurrence after liver transplantation and significant prolongation of survival were observed in the Y-27632-treated rats in comparison with theY-27632-untreated rats. Tacrolimus stimulates the Rho/ROCK signal pathway to enhance the invasiveness of hepatocellular carcinoma, and the ROCK inhibitor Y-27632 can be used as a new antimetastatic agent for the prevention of tumor recurrence after liver transplantation.

肝移植术后肿瘤复发仍然是肝细胞癌患者的一个重要问题。小GTPase Rho/Rho相关激酶（ROCK）通路参与癌细胞的运动和侵袭。我们研究了他克莫司是否激活Rho/ROCK信号通路促进大鼠肝癌细胞的侵袭。我们还研究了ROCK抑制剂Y-27632是否能抑制实验性肝移植大鼠肝癌模型后的肿瘤复发。采用肝癌细胞系mca - rh7777移植术对大鼠进行原位肝移植。肝移植大鼠给予他克莫司治疗，将大鼠分为y -27632治疗组（10mg/kg，连续28天）和y -27632治疗组。他克莫司增强了癌细胞的迁移，并刺激了肌球蛋白轻链（MLC）的磷酸化，这是Rho/ROCK信号传导的下游效应。Y-27632抑制癌细胞迁移和他克莫司诱导的MLC磷酸化。与未使用y -27632的大鼠相比，y -27632治疗的大鼠肝移植后肿瘤复发受到抑制，生存期明显延长。他克莫司刺激Rho/ROCK信号通路，增强肝细胞癌的侵袭性，ROCK抑制剂Y-27632可作为一种新的抗转移药物，预防肝移植后肿瘤复发。