Carpenter Richard L, Lo Hui-Wen
Department of Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, North Carolina 27710, USA.
Discov Med. 2012 Feb;13(69):105-13.
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.
刺猬信号通路调节正常细胞的生长和分化。当该通路失调时，会导致肿瘤发生，并支持人类癌症更具侵袭性的表型，如进展、转移和治疗抗性。锌指转录因子的胶质瘤相关癌基因同源物1（GLI1）家族是刺猬信号通路的核介质，可调节肿瘤发生和进展各个阶段所必需的基因。因此，刺猬信号通路的几个成分是癌症治疗的主要靶点，包括GLI1和 smoothened。尽管GLI1基因最初是在胶质母细胞瘤中被鉴定为扩增基因，但其扩增相对罕见。尚未报道GLI1基因存在体细胞突变。值得注意的是，在GLI1基因发现二十年后，最近发现GLI1转录本会发生可变剪接，形成两种较短的异构体，一种是N端缺失变体（GLI1ΔN）和一种截短的GLI1（tGLI1）。这些变体似乎具有不同的组织表达模式和功能。最值得注意的是，tGLI1异构体表现为功能获得性GLI1，可诱导不受GLI1调控的基因表达，并促进更具侵袭性的癌症表型。因此，本综述将重点关注这些异构体之间的结构和功能差异，以及它们对重要癌细胞特征的贡献，包括增殖、运动、侵袭和血管生成。
