The Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
Faculty of Medicine, The University of Queensland, Brisbane, Queensland 4072, Australia.
Carcinogenesis. 2021 Apr 17;42(3):357-368. doi: 10.1093/carcin/bgaa139.
Nuclear factor one (NFI) transcription factors are implicated in both brain development and cancer in mice and humans and play an essential role in glial differentiation. NFI expression is reduced in human astrocytoma samples, particularly those of higher grade, whereas over-expression of NFI protein can induce the differentiation of glioblastoma cells within human tumour xenografts and in glioblastoma cell lines in vitro. These data indicate that NFI proteins may act as tumour suppressors in glioma. To test this hypothesis, we generated complex mouse genetic crosses involving six alleles to target gene deletion of known tumour suppressor genes that induce endogenous high-grade glioma in mice, and overlaid this with loss of function Nfi mutant alleles, Nfia and Nfib, a reporter transgene and an inducible Cre allele. Deletion of Nfi resulted in reduced survival time of the mice, increased tumour load and a more aggressive tumour phenotype than observed in glioma mice with normal expression of NFI. Together, these data indicate that NFI genes represent a credible target for both diagnostic analyses and therapeutic strategies to combat high-grade glioma.
核因子一 (NFI) 转录因子在小鼠和人类的大脑发育和癌症中都有涉及，并且在神经胶质分化中发挥着重要作用。NFI 的表达在人类星形细胞瘤样本中降低，特别是在高级别样本中，而 NFI 蛋白的过表达可以诱导人类肿瘤异种移植物中的神经胶质瘤细胞和体外神经胶质瘤细胞系的分化。这些数据表明，NFI 蛋白可能在神经胶质瘤中作为肿瘤抑制因子发挥作用。为了验证这一假说，我们生成了涉及六个等位基因的复杂小鼠遗传杂交，以靶向已知的在小鼠中诱导内源性高级别神经胶质瘤的肿瘤抑制基因的缺失，并与功能丧失的 Nfi 突变等位基因 Nfia 和 Nfib、报告基因转染体和可诱导 Cre 等位基因叠加。Nfi 的缺失导致小鼠的存活时间缩短，肿瘤负荷增加，并且肿瘤表型比 NFI 正常表达的神经胶质瘤小鼠更为侵袭性。总之，这些数据表明，NFI 基因是诊断分析和治疗策略的一个有价值的靶点，可用于对抗高级别神经胶质瘤。
