Targeting alpha-fetoprotein represses the proliferation of hepatoma cells via regulation of the cell cycle
Targeting alpha-fetoprotein represses the proliferation of hepatoma cells via regulation of the cell cycle
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DOI：
10.1016/j.cca.2008.04.012
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发表时间：
2008-08-01
影响因子：
5
通讯作者：
Li, Xin
中科院分区：
文献类型：
--
作者：
Tang, Hua;Tang, Xiao-Yan;Li, Xin
背景：AFP是原发性肝癌的生物标志物，但对其在肝癌发病机制中的作用知之甚少。我们研究了AFP如何调节肝癌细胞的增殖。方法：创建了表达针对AFP的siRNA的重组腺病毒。分别通过集落形成试验和 SCID 小鼠肿瘤异种移植来检测体外细胞增殖的抑制和体内肝癌生长的抑制。通过流式细胞术测定细胞周期。通过微阵列测定表达谱。结果：靶向降低AFP表达的siRNA特异性地、显着地抑制肝癌细胞的增殖。使用 Adv-AFPsiRNA 进行局部治疗可显着抑制 SCID 小鼠异种移植物中肝癌来源的 HepG2 细胞的生长。敲低AFP导致细胞周期G(1)/S转变明显延迟，但不影响HepG2细胞的凋亡。鉴定出SKP2、Cyclin D1、Csk、EBAG9等与细胞周期相关的基因。结论：内源性AFP是肝癌细胞生长的关键决定因素，通过调节细胞周期发挥作用。这项研究表明，用 siRNA 靶向 AFP 可能是肝癌的潜在治疗方法。 (C) 2008 Elsevier B.V. 保留所有权利。
Background: AFP is a biomarker for primary liver cancer, yet little is known about its effect in the pathogenesis of hepatoma. We examined how AFP modulates the proliferation of hepatoma cells.Methods: Recombinant adenovirus expressing siRNA against AFP was created. The repression of cell proliferation in vitro and growth of hepatoma in vivo were examined by colony formation assay and tumor xenograft in SCID mice, respectively. Cell cycle was assayed by flow cytometry. Expression profile was determined by microarrays.Results: siRNA targeting reduced expression of AFP specifically and markedly inhibited the proliferation of hepatoma cells. Local treatment using Adv-AFPsiRNA caused significant repression of the growth of hepatoma derived HepG2 cells in xenograft in SCID mice. Knockdown of AFP resulted in an obvious delay in the G(1)/S transition of cell cycle, but did not affect apoptosis in HepG2 cells. Some genes related to the cell cycle, including SKP2, Cyclin D1, Csk and EBAG9 were identified.Conclusions: The endogenous AFP is a critical determinant of the growth of hepatoma cells, which functions by regulating the cell cycle. This study suggests that targeting of AFP with siRNA could be a potential therapeutic approach for hepatoma. (C) 2008 Elsevier B.V. All rights reserved.