Wang Zheng, Zhou Jian, Fan Jia, Tan Chang-Jun, Qiu Shuang-Jian, Yu Yao, Huang Xiao-Wu, Tang Zhao-You
Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, People's Republic of China.
J Cancer Res Clin Oncol. 2009 May;135(5):715-22. doi: 10.1007/s00432-008-0506-z. Epub 2008 Nov 11.
Immunosuppressive therapy after liver transplantation for hepatocellular carcinoma (HCC) is one of the major contributory factors for HCC recurrence and metastasis. Sirolimus, a potent immunosuppressant, has been reported to be an effective inhibitor in a variety of tumors. The present study is designed to explore whether sirolimus could block the growth and metastatic progression of HCC.
MHCC97H cells were used as targets to explore the effect of sirolimus on cell cycle progression, apoptosis, proliferation, and its antiangiogenic mechanism. LCI-D20, a highly metastatic model of human HCC in nude mice, was also used as the model tumor to explore the effect of sirolimus on tumor growth and metastatic progression.
In vitro, sirolimus induced cell cycle arrest at the G1 checkpoint and blocked proliferation of MHCC97H cells but did not induce apoptosis. In vivo, sirolimus prevented tumor growth and metastatic progression in LCI-D20. Intratumoral microvessel density and circulating levels of VEGF in tumor-bearing mice were also significantly reduced in sirolimus treatment group. Quantitative RT-PCR showed that sirolimus down-regulated the mRNA expression of VEGF and HIF-1a, but not of bFGF, and TGF-b in MHCC97H cells. Furthermore, western blot analysis confirmed that sirolimus also decreased expression of HIF-1a at protein level, in parallel with the down-regulation of the levels of VEGF protein excretion in a time-dependent manner as compared to untreated control cells following anoxia.
The immunosuppressive macrolide sirolimus prevents the growth and metastatic progression of HCC, and suppresses VEGF synthesis and secretion by downregulating HIF-1a expression. Sirolimus may be useful for clinical application in patients who received a liver transplant for HCC.
肝细胞癌（HCC）肝移植后的免疫抑制治疗是HCC复发和转移的主要促成因素之一。西罗莫司是一种强效免疫抑制剂，据报道在多种肿瘤中是一种有效的抑制剂。本研究旨在探讨西罗莫司是否能阻断HCC的生长和转移进程。
以MHCC97H细胞为靶点，探讨西罗莫司对细胞周期进程、凋亡、增殖及其抗血管生成机制的影响。LCI-D20是人HCC在裸鼠中的高转移模型，也用作模型肿瘤，探讨西罗莫司对肿瘤生长和转移进程的影响。
在体外，西罗莫司诱导细胞周期停滞在G1期检查点并阻断MHCC97H细胞的增殖，但不诱导凋亡。在体内，西罗莫司可预防LCI-D20肿瘤的生长和转移进程。西罗莫司治疗组荷瘤小鼠的瘤内微血管密度和循环中VEGF水平也显著降低。定量RT-PCR显示，西罗莫司下调了MHCC97H细胞中VEGF和HIF-1α的mRNA表达，但未下调bFGF和TGF-β的表达。此外，蛋白质印迹分析证实，与缺氧后未处理的对照细胞相比，西罗莫司还以时间依赖性方式降低了HIF-1α在蛋白质水平的表达，同时VEGF蛋白质分泌水平也下调。
免疫抑制大环内酯类药物西罗莫司可预防HCC的生长和转移进程，并通过下调HIF-1α表达抑制VEGF的合成和分泌。西罗莫司可能对接受HCC肝移植的患者具有临床应用价值。
