Suppressing Wnt signaling by the hedgehog pathway through sFRP-1
Suppressing Wnt signaling by the hedgehog pathway through sFRP-1
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DOI：
10.1074/jbc.c600200200
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发表时间：
2006-11-24
影响因子：
4.8
通讯作者：
Xie, Jingwu
中科院分区：
文献类型：
--
作者：
He, Jing;Sheng, Tao;Xie, Jingwu
Hedgehog（Hh）信号通路在胚胎发育和癌变过程中起重要作用。已经在几种类型的胃肠癌中鉴定出Hh信号传导的激活，包括食管癌、胃癌、胰腺癌和肝癌。最近的一些研究表明，Hh信号传导激活可以抑制Wnt信号传导。然而，这种抑制的分子基础仍然不清楚。作为Hh信号通路中的转录因子，Gli分子在培养中转化细胞，并且它们的表达与癌症发展相关。在这里，我们报告的分泌卷曲相关蛋白sFRP-1在小鼠胚胎成纤维细胞的表达依赖于Gli 1和Gli 2。在人胃癌细胞中，Hh信号的抑制降低了sFRP-1转录水平，而Gli 1的异位表达增加了sFRP-1转录水平。染色质免疫沉淀的结果表明，Gli 1参与sFRP-1的转录调控。在Gli 1表达的293细胞中，Wnt-1介导的β-连环蛋白在胞质溶胶中的积累和DKK 1表达都被废除，这可以通过抑制sFRP-1表达来逆转。此外，虽然SIIA细胞对Wnt-1条件培养基没有反应，但平滑（SMO）拮抗剂KAAD-环巴胺（酮基-N-氨基乙基氨基己酰基二氢肉桂酰基环巴胺）抑制Hh信号传导导致Wnt 1介导的β-连环蛋白在胞质溶胶中积累。这些数据表明，sFRP-1，刺猬途径的靶基因，参与了刺猬途径和Wnt途径之间的串扰。
The hedgehog (Hh) signaling pathway is essential for embryonic development and carcinogenesis. Activation of Hh signaling has been identified in several types of gastrointestinal cancers, including esophageal, gastric, pancreatic, and liver cancers. Several recent studies suggest that Hh signaling activation can inhibit Wnt signaling. However, the molecular basis underlying this inhibition remains unclear. As transcription factors in the Hh signaling pathway, Gli molecules transform cells in culture, and their expression are associated with cancer development. Here we report that expression of a secreted frizzled-related protein-sFRP-1 in mouse embryonic fibroblasts is dependent on Gli1 and Gli2. In human gastric cancer cells, inhibition of Hh signaling reduces the level of sFRP-1 transcript, whereas ectopic expression of Gli1 increases the level of sFRP-1 transcript. Results from chromatin immunoprecipitation indicate that Gli1 is involved in transcriptional regulation of sFRP-1. In 293 cells with Gli1 expression, Wnt-1-mediated beta-catenin accumulation in the cytosol and DKK1 expression are all abrogated, which can be reversed by inhibiting sFRP-1 expression. Furthermore, while SIIA cells do not respond to Wnt-1-conditioned medium, inhibition of Hh signaling by smoothened (SMO) antagonist KAAD-cyclopamine (keto-N-aminoethylaminocaproyldihydrocinnamoylcyclopamine) leads to Wnt1-mediated beta-catenin accumulation in the cytosol. These data indicate that sFRP-1, a target gene of the hedgehog pathway, is involved in cross-talk between the hedgehog pathway and the Wnt pathway.