Hedgehog pathway and GLI1 isoforms in human cancer.
Hedgehog pathway and GLI1 isoforms in human cancer.
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DOI：
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发表时间：
2012-02
影响因子：
1.4
通讯作者：
R. Carpenter;H. Lo
中科院分区：
文献类型：
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作者：
R. Carpenter;H. Lo
Hedgehog信号通路调节正常细胞生长和分化。当去调控时，Hedgehog通路导致肿瘤发生并支持人类癌症的更具侵袭性的表型，如进展、转移和治疗抗性。神经胶质瘤相关癌基因同源物1（GLI1）家族的锌指转录因子是刺猬途径的核介质，调节基因的各个阶段的肿瘤的发展和进展。因此，Hedgehog通路的几个组分是癌症治疗的主要靶点，包括GLI1和smoothened。虽然GLI1基因最初被鉴定为胶质母细胞瘤中的扩增基因，但发现其扩增相对罕见。在GLI1基因中没有报道体细胞突变。值得注意的是，在发现GLI1基因20年后，最近发现GLI1转录物经历选择性剪接，形成两种较短的同种型，N末端缺失变体（GLI1ΔN）和截短的GLI1（tGLI1）。这些变体似乎具有不同的组织表达和功能模式。最值得注意的是，tGLI1亚型表现为功能获得性GLI1，可以诱导不受GLI1调节的基因表达，并促进更具侵袭性的癌症表型。因此，本次审查将集中在这些异构体之间的结构和功能差异，以及它们对重要的癌细胞特性，包括增殖，运动，侵袭和血管生成的贡献。
The Hedgehog signaling pathway regulates normal cell growth and differentiation. When deregulated, the Hedgehog pathway leads to tumorigenesis and supports more aggressive phenotypes of human cancers, such as progression, metastasis, and therapeutic resistance. The glioma-associated oncogene homolog 1 (GLI1) family of zinc finger transcription factors is the nuclear mediator of the Hedgehog pathway that regulates genes essential for various stages of tumor development and progression. Consequently, several components of the Hedgehog pathway are major targets of cancer therapy, including GLI1 and smoothened. Although the GLI1 gene was initially identified as an amplified gene in glioblastoma, its amplification was found to be relatively rare. No somatic mutations have been reported in the GLI1 gene. Notably, two decades after the discovery of the GLI1 gene, the GLI1 transcript was recently found to undergo alternative splicing forming two shorter isoforms, an N-terminal deletion variant (GLI1ΔN) and a truncated GLI1 (tGLI1). These variants appear to have different patterns of tissue expression and functions. Most notably, the tGLI1 isoform behaves as a gain-of-function GLI1 that can induce expression of genes not regulated by GLI1 and promotes more aggressive cancer phenotypes. Therefore, this review will focus on the structural and functional differences between these isoforms, and also on their contributions to important cancer cell characteristics, including proliferation, motility, invasion, and angiogenesis.