Rho-associated kinase inhibitor reduces tumor recurrence after liver transplantation in a rat hepatoma model
Rho-associated kinase inhibitor reduces tumor recurrence after liver transplantation in a rat hepatoma model
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DOI：
10.1111/j.1600-6143.2006.01647.x
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发表时间：
2007-02-01
影响因子：
8.8
通讯作者：
Asahara, T.
中科院分区：
文献类型：
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作者：
Ogawa, T.;Tashiro, H.;Asahara, T.
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GT3/Rho相关激酶（ROCK）通路参与癌细胞的运动性和侵袭性。我们研究了他克莫司是否激活Rho/ROCK信号通路以促进大鼠肝癌细胞的侵袭力。我们还研究了ROCK抑制剂Y-27632是否抑制大鼠肝细胞癌模型实验性肝移植后的肿瘤复发。建立了肝癌细胞系McA-RH 7777荷瘤大鼠原位肝移植模型。将他克莫司给予肝移植大鼠，并将这些大鼠分为两组：Y-27632治疗组（10 mg/kg，持续28天）和Y-27632未治疗组。他克莫司增强癌细胞迁移并刺激肌球蛋白轻链（MLC）的磷酸化，肌球蛋白轻链是Rho/ROCK信号传导的下游效应物。Y-27632抑制癌细胞迁移和他克莫司诱导的MLC磷酸化。与Y-27632未处理的大鼠相比，在Y-27632处理的大鼠中观察到肝移植后肿瘤复发的抑制和生存期的显著延长。他克莫司通过激活Rho/ROCK信号通路增强肝癌的侵袭性，ROCK抑制剂Y-27632可作为一种新的抗转移药物用于预防肝移植后肿瘤复发。
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 (10 mg/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.