Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation
Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation
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DOI：
10.1038/sj.onc.1210513
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发表时间：
2007-11-01
期刊：
影响因子：
8
通讯作者：
Mishra, L.
中科院分区：
文献类型：
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作者：
Kitisin, K.;Ganesan, N.;Mishra, L.
转化生长因子- β (tgf - β)信号成员，tgf - β受体II型（TBRII）， Smad2， Smad4和Smad接头，胚胎肝fodrin (ELF)，是胃肠道癌症中重要的肿瘤抑制因子。在这里，我们发现40%的elf（-+/-）小鼠自发发展为肝细胞癌（HCC），细胞周期蛋白D1、细胞周期蛋白依赖性激酶4 （Cdk4）、c-Myc和MDM2的表达显著增加。9例人hcc中有8例出现ELF降低，但未出现TBRII或Smad4 （P < 0.017）。在人肝癌细胞系SNU-398和SNU-475中，ELF和TBRII也显著降低。在SNU-398细胞中，ELF和TBRII的恢复可显著降低细胞周期蛋白D1和过度磷酸化的视网膜母细胞瘤（hyperphosphoryated - prb）。因此，我们发现TGF-b信号和Smad接头ELF抑制人类肝癌的发生，可能是通过cyclin D1的失调。ELF的缺失可能是向完全转化表型进展的主要事件，并可能为人类hcc的新治疗方法带来希望。
Transforming growth factor-beta (TGF-beta) signaling members, TGF-beta receptor type II ( TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin ( ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf(-+/-) mice spontaneously develop hepatocellular cancer ( HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (P < 0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma ( hyperphosphorylated-pRb). Thus, we show that TGF-b signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.