Alpha-fetoprotein: a new member of intracellular signal molecules in regulation of the PI3K/AKT signaling in human hepatoma cell lines
Alpha-fetoprotein: a new member of intracellular signal molecules in regulation of the PI3K/AKT signaling in human hepatoma cell lines
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DOI：
10.1002/ijc.25373
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发表时间：
2011-02-01
影响因子：
6.4
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Li, Mengsen;Li, Hui;Li, Gang
尽管细胞质甲胎蛋白(AFP)在胎肝发育和肝肿瘤发生中作为血清生长因子的作用已明确，但其生物学意义仍不完全清楚。在此，我们提供的证据表明，细胞质AFP可能在人肝癌细胞的磷脂酰肌醇3-激酶(PI3K)/AKT通路中发挥调节作用。结果表明，AFP与10号染色体缺失的磷酸酶和张力蛋白同源物(PTEN)在产生AFP的Bel 7402和HepG2细胞的胞浆内共定位和相互作用，用荧光共振能量转移技术测定相互作用距离为12.6+/-2.7埃。全反式维甲酸抑制AFP的表达或下调AFP的表达均可导致PTEN水平升高，同时AKT磷酸化水平降低。将AFP基因导入HLE细胞(最初为AFP阴性)，可显著激活AKT信号转导通路。LY 294002对PI3K信号转导的抑制作用被转染组同时被逆转，并伴随着全反式维甲酸诱导的PTEN上调和细胞生长的增强。综上所述，这些结果表明胞浆AFP参与了肝细胞生长和肿瘤发生的调控。
Despite its well-defined role as a serum growth factor during fetal liver development and hepatic oncogenesis, the biological significance of cytoplasmic alpha-fetoprotein (AFP) remains incompletely understood. Here, we provide evidence to illustrate that cytoplasmic AFP may function as a regulator in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in human hepatocellular carcinoma cells. The results demonstrated colocalization and interaction of AFP and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in the cytoplasm of AFP-producing Bel 7402 and HepG2 cells, with an interaction distance of 12.6 +/- 2.7 angstrom as determined with the fluorescence resonance energy transfer technique. Knockdown of AFP mRNA or inhibition of AFP expression by all trans-retinoic acid resulted in enhancement of the PTEN level with a synchronous decrease in phosphorylated AKT. Transfection of the afp gene into HLE cells (originally AFP negative) led to a significant activation of AKT signaling. The inhibition of PI3K signaling by LY 294002 was simultaneously reversed by transfection, accompanied by diminution of all trans-retinoic acid-induced upregulation of PTEN and enhancement of cell growth. In conclusion, these results demonstrate that cytoplasmic AFP is involved in regulation of hepatocellular growth and tumorigenesis.