Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis
Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis
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DOI：
10.1093/carcin/bgi292
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发表时间：
2006-04-01
期刊：
影响因子：
4.7
通讯作者：
Diehl, AM
中科院分区：
文献类型：
--
作者：
Sicklick, JK;Li, YX;Diehl, AM
Hhedgehog(HH)途径的激活促进了多种内胚层来源组织的肿瘤发生，但其在肝细胞癌发病机制中的作用尚不清楚。虽然正常肝细胞缺乏HH信号，但内胚层前体细胞中的HH通路的激活是肝脏发育所必需的。因此，我们推测肝癌的发生可能涉及HH信号的调节。当HH配体与其受体Patted(PTC)结合时，该途径被激活。在未被占据的状态下，PTC通常作为一种肿瘤抑制因子，抑制原癌蛋白SMO激活下游成分和靶基因的转录。在这里，我们发现在肝癌中，Smo原癌基因的过度表达，以及Smo/PTC mRNA水平化学计量比的增加，与肿瘤大小相关，这是肝癌生物学中的一个预后指标。在一个肿瘤中，我们在进化上保守的残基中发现了一种新的Smo突变。我们还证明了肝癌细胞株(HepG2和Hep3B)表达HH途径组分并激活了HH转录靶点。在Hep3B细胞中，野生型SMO的抑制剂环丙胺无作用，而致癌SMO的阻断剂KAAD-环胺可抑制HH信号转导活性50%，使肝癌基因c-myc的表达减少8倍，并使Hep3B细胞的生长抑制94%。这些数据支持我们的假设，即HH信号在人类肝癌的发生中处于失调状态。我们证明了Smo原癌基因的过度表达和/或致癌激活介导了c-myc的过度表达，c-myc在肝癌的发生中起着关键作用，并提示Smo是肝癌发生的预后因素。
Hedgehog (Hh) pathway activation promotes tumors in several endodermally derived tissues, but its role in the pathogenesis of hepatocellular carcinoma (HCC) is unknown. Although normal hepatocytes lack Hh signaling, activation of the Hh pathway in endodermal progenitors is required for liver development. Thus, we hypothesized that hepatocarcinogenesis may involve regulation of Hh signaling. This pathway is activated when Hh ligand binds to its receptor, Patched (PTC). In an unoccupied state, PTC normally functions as a tumor suppressor that inhibits Smoothened (SMO), a proto-oncoprotein, from activating downstream components and transcription of target genes. Here we show that in HCCs, overexpression of the Smo proto-oncogene, as well as an increase in the stoichiometric ratio of Smo to Ptc mRNA levels, correlated with tumor size, a prognostic indicator in HCC biology. In one tumor we identified a novel Smo mutation in an evolutionarily conserved residue. We also demonstrated that HCC cell lines (HepG2 and Hep3B) expressed Hh pathway components and activated Hh transcriptional targets. In Hep3B cells, cyclopamine, an inhibitor of wild-type SMO, had no effect, but KAAD-cyclopamine, a blocker of oncogenic SMO, inhibited Hh signaling activity by 50%, decreased expression of the hepatocarcinogenic oncogene, c-myc, by 8-fold, and inhibited the growth rate of Hep3B cells by 94%. These data support our hypothesis that Hh signaling is dysregulated in human hepatocarcinogenesis. We demonstrate that overexpression and/or tumorigenic activation of the Smo proto-oncogene mediates c-myc overexpression which plays a critical role in hepatocarcinogenesis and suggests that Smo is a prognostic factor in HCC tumorigenesis.