Blockage of HGF/c-Met system by gene therapy (adenovirus-mediated NK4 gene) suppresses hepatocellular carcinoma in mice
Blockage of HGF/c-Met system by gene therapy (adenovirus-mediated NK4 gene) suppresses hepatocellular carcinoma in mice
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DOI：
10.1016/j.jhep.2006.04.011
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发表时间：
2006-11-01
影响因子：
25.7
通讯作者：
Fujimoto, Jiro
中科院分区：
文献类型：
--
作者：
Son, Gakuhei;Hirano, Tadamichi;Fujimoto, Jiro
背景/目的：肝细胞生长因子通过促进细胞运动和血管生成作用促进肿瘤的发展。肝细胞生长因子片段NK4作为其受体拮抗剂。方法：用腺病毒(AdCMV.N1K4)介导NK4基因转导人肝癌细胞株Huh7。以LacZ表达型腺病毒(AdCMV.LacZ)为对照。首先在体外研究了NK4对HuH7细胞的作用。建立裸鼠Huh7皮下移植瘤模型，分别注射AdCMV.NK4(n=6)和AdCMV.LacZ(n=6)。最后，将Huh7细胞注射到严重联合免疫缺陷小鼠的门静脉建立肝肿瘤模型后，系统注射AdCMV.NK4(n=6)或AdCMV.LacZ(n=6)。结果：NK4抑制肝细胞生长因子诱导的Huh7细胞c-Met的磷酸化。NK4可抑制Huh7细胞的侵袭和迁移，抑制皮下移植瘤和肝移植瘤的生长(p<；0.001，p<；0.01)，并提高小鼠的存活率(p<；0.05)。结论：NK4抑制肿瘤细胞的运动和血管生成，对小鼠肝内移植瘤的生长有明显的抑制作用。因此，NK4基因治疗在肝细胞癌的治疗中显示出明显的前景。(C)2006年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background/Aims:Hepatocyte growth factor promotes cancer development through cell motility-promoting and angiogenic effects. NK4, a fragment of hepatocyte growth factor, acts as its receptor antagonist. We assessed effects of NK4 gene therapy against human hepatocellular carcinoma cells (HUH7) transplanted into mice.Methods: NK4 gene transduction was mediated by adenovirus (AdCMV.N1K4). LacZ expression adenovirus (AdCMV.LacZ) was used as a control. NK4 effects on HUH7 cells first were studied in vitro. Subcutaneous HUH7 tumors established in athymic nude mice were injected with AdCMV.NK4 (n = 6) or AdCMV.Lacz (n = 6). Finally, after HUH7 cells were injected into the portal vein in mice with severe combined immunodeficiency to establish hepatic tumors, mice systemically were injected with AdCMV.NK4 (n = 6) or AdCMV.LacZ (n = 6).Results: NK4 inhibited hepatocyte growth factor-induced phosphorylation of c-Met in HUH7 cells. Invasion and migration of HUH7 cells were inhibited by NK4 transfection, which also suppressed growth of transplanted subcutaneous and liver tumors (p < 0.001, p < 0.01 respectively), and improved mouse survival (p < 0.05). Angiogenesis assessed by small vessel density was significantly decreased in the NK4-treated group.Conclusions: NK4 inhibited tumor cell motility and angiogenesis, greatly suppressing growth of HUH7 tumors transplanted into mouse liver. NK4 gene therapy thus showed apparent promise for treatment of hepatocellular carcinoma. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.