Second Department of Surgery, Faculty of Medicine, Hiroshima University, Hiroshima, Japan.
Transplantation. 2009 Oct 27;88(8):980-6. doi: 10.1097/TP.0b013e3181b9ca69.
BACKGROUND.: Although the outcome of liver transplant patients with hepatocellular carcinoma (HCC) has improved with the introduction of strict criteria, tumor recurrence still remains a significant problem. Sphingosine-1-phosphate (S1P) is a phospholipid mediator that can induce diverse cellular responses, such as proliferation, migration, adhesion, and cell-rounding, in cancer cells. We investigated whether FTY720, a S1P analog, suppresses tumor recurrence after experimental liver transplantation in a rat HCC model. METHODS.: HCC-bearing rats were subjected to orthotropic liver transplantation. HCC cells were analyzed for cell migration, proliferation, and S1P receptors. RESULTS.: FTY720 induced the down-regulation of the S1P-1 receptor of HCC cells and suppressed both cancer cell migration and proliferation. FTY720 also suppressed mitogen-activated protein kinase phosphorylation. The suppression of tumor recurrence after liver transplantation and a significant prolongation of survival were observed in the FTY720-treated rats, in comparison with FTY720-untreated rats. CONCLUSION.: FTY720 suppresses the invasiveness and proliferation of HCC through a down-regulating S1P-1 receptor to suppress the recurrence of HCC after liver transplantation; FTY720 may be used as a new antimetastatic agent for the prevention of tumor recurrence after liver transplantation.
尽管随着严格标准的引入，肝移植患者肝癌（HCC）的预后有所改善，但肿瘤复发仍然是一个重大问题。 1-磷酸鞘氨醇（S1P）是一种磷脂介质，可诱导癌细胞发生多种细胞反应，如增殖、迁移、黏附和细胞变圆。我们研究了 S1P 类似物 FTY720 是否可以抑制大鼠 HCC 模型实验性肝移植后肿瘤的复发。
携带 HCC 的大鼠接受原位肝移植。分析 HCC 细胞的迁移、增殖和 S1P 受体。
FTY720 诱导 HCC 细胞 S1P-1 受体下调，并抑制癌细胞迁移和增殖。FTY720 还抑制丝裂原活化蛋白激酶磷酸化。与未用 FTY720 治疗的大鼠相比，用 FTY720 治疗的大鼠肝移植后肿瘤复发得到抑制，生存时间显著延长。
FTY720 通过下调 S1P-1 受体抑制 HCC 的侵袭和增殖，从而抑制肝移植后 HCC 的复发；FTY720 可能被用作预防肝移植后肿瘤复发的新的抗转移药物。
