Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (Review)
Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (Review)
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DOI：
10.3892/ijmm_00000019
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发表时间：
2008-09-01
影响因子：
5.4
通讯作者：
Katoh, Masaru
中科院分区：
文献类型：
--
作者：
Katoh, Yuriko;Katoh, Masaru
SHH、IHH和DHH是与Patched受体以及CDON、BOC或GAS 1共受体结合的脂质修饰的分泌蛋白。在没有Hedgehog信号传导的情况下，GLI 1被转录抑制，GLI 2被GSK 3和CK 1磷酸化，用于FBXW 11（β TRCP 2）介导的降解，GLI 3被加工成切割的阻遏物。在Hedgehog信号传导的存在下，Smoothened由于Patched的Hedgehog依赖性内化而从Patched介导的抑制中释放，这导致MAP 3 K10（MST）激活和SUFU失活，用于GLI家族成员的稳定和核积累。然后，GLI激活剂上调CCND 1、CCND 2以加速细胞周期，上调FOXA 2、FOXC 2、FOXE 1、FOXF 1、FOXL 1、FOXP 3、POU 3F 1、RUNX 2、SOX 13、TBX 2以确定细胞命运，上调JAG 2、INHBC和INHBE以调节干细胞信号传导。Hedgehog信号还上调间充质细胞中的SFRP 1，用于EMT信号调节。上皮-间质转化（Epithelial-to-mesenchymal transition，EMT）是胚胎发育、成体组织稳态和肿瘤发生过程中的一个重要环节，其特征是E-cadherin向N-cadherin的类别转换。SNAI 1（Snail）、SNAI 2（Slug）、SNAI 3、ZEB 1、ZEB 2（SIP 1）、KLF 8、TWIST 1和TWIST 2是抑制编码E-钙粘蛋白的CDH 1基因的EMT调节剂。Hedgehog信号诱导Notch-CSL介导的SNAI 1上调的JAG 2上调，并且还通过TGF β受体和NF-κ B诱导ZEB 1和ZEB 2上调的TGF β 1分泌。TGF β介导的miR-141、miR-200 a、miR-200 b、miR-200 c、miR-205和miR-429的下调导致ZEB 1和ZEB 2蛋白的上调。Hedgehog信号传导激活通过FGF、Notch、TGF β信号传导级联和miRNA调控网络间接导致EMT。靶向干细胞信号传导组分或EMT调节剂的miRNA是有效的药物靶标;然而，在合成miRNA的临床应用之前，应严格控制脱靶效应。肽模拟物和RNA适体也可用作Hedgehog信号传导抑制剂或EMT抑制剂。
SHH, IHH, and DHH are lipid-modified secreted proteins binding to Patched receptors, and CDON, BOC or GAS1 co-receptors. In the absence of Hedgehog signaling, GLI1 is transcriptionally repressed, GLI2 is phosphorylated by GSK3 and CK1 for the FBXW11 (beta TRCP2)-mediated degradation, and GLI3 is processed to a cleaved repressor. In the presence of Hedgehog signaling, Smoothened is relieved from Patched-mediated suppression due to the Hedgehog-dependent internalization of Patched, which leads to MAP3K10 (MST) activation and SUFU inactivation for the stabilization and nuclear accumulation of GLI family members. GLI activators then upregulate CCND1, CCND2 for cell cycle acceleration, FOXA2, FOXC2, FOXE1, FOXF1, FOXL1, FOXP3, POU3F1, RUNX2, SOX13, TBX2 for cell fate determination, JAG2, INHBC, and INHBE for stem cell signaling regulation. Hedgehog signals also upregulate SFRP1 in mesenchymal cells for EMT signaling regulation. Epithelial-to-mesenchymal transition (EMT) during embryogenesis, adult tissue homeostasis and carcinogenesis is characterized by class switch from E-cadherin to N-cadherin. SNAI1 (Snail), SNAI2 (Slug), SNAI3, ZEB1, ZEB2 (SIP1), KLF8, TWIST1, and TWIST2 are EMT regulators repressing CDH1 gene encoding E-cadherin. Hedgehog signals induce JAG2 upregulation for Notch-CSL-mediated SNAI1 upregulation, and also induce TGF beta 1 secretion for ZEB1 and ZEB2 upregulation via TGF beta receptor and NF-kappa B. TGF beta-mediated downregulation of miR-141, miR-200a, miR-200b, miR-200c, miR-205, and miR-429 results in upregulation of ZEB1 and ZEB2 proteins. Hedgehog signaling activation indirectly leads to EMT through FGF, Notch, TGF beta signaling cascades, and miRNA regulatory networks. miRNAs targeted to stem cell signaling components or EMT regulators are potent drug targets; however, off-target effects should be strictly controlled before clinical application of synthetic miRNA. Peptide mimetic and RNA aptamer could also be utilized as Hedgehog signaling inhibitors or EMT suppressors.