Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
Biol Open. 2014 Sep 12;3(10):937-46. doi: 10.1242/bio.20148193.
Autocrine activation of the Wnt/β-catenin pathway occurs in several cancers, notably in breast tumors, and is associated with higher expression of various Wnt ligands. Using various inhibitors of the FZD/LRP receptor complex, we demonstrate that some adenosquamous carcinomas that develop in MMTV-CUX1 transgenic mice represent a model for autocrine activation of the Wnt/β-catenin pathway. By comparing expression profiles of laser-capture microdissected mammary tumors, we identify Glis1 as a transcription factor that is highly expressed in the subset of tumors with elevated Wnt gene expression. Analysis of human cancer datasets confirms that elevated WNT gene expression is associated with high levels of CUX1 and GLIS1 and correlates with genes of the epithelial-to-mesenchymal transition (EMT) signature: VIM, SNAI1 and TWIST1 are elevated whereas CDH1 and OCLN are decreased. Co-expression experiments demonstrate that CUX1 and GLIS1 cooperate to stimulate TCF/β-catenin transcriptional activity and to enhance cell migration and invasion. Altogether, these results provide additional evidence for the role of GLIS1 in reprogramming gene expression and suggest a hierarchical model for transcriptional regulation of the Wnt/β-catenin pathway and the epithelial-to-mesenchymal transition.
自分泌激活的 Wnt/β-catenin 通路发生在几种癌症中，特别是在乳腺癌中，并且与各种 Wnt 配体的高表达有关。使用 FZD/LRP 受体复合物的各种抑制剂，我们证明了在 MMTV-CUX1 转基因小鼠中发展的一些腺鳞癌代表了 Wnt/β-catenin 通路的自分泌激活模型。通过比较激光捕获显微解剖的乳腺肿瘤的表达谱，我们确定 Glis1 是一种转录因子，在具有升高的 Wnt 基因表达的肿瘤亚集中高度表达。对人类癌症数据集的分析证实，升高的 WNT 基因表达与高水平的 CUX1 和 GLIS1 相关，并与上皮-间充质转化 (EMT) 特征的基因相关：VIM、SNAI1 和 TWIST1 升高，而 CDH1 和 OCLN 降低。共表达实验表明，CUX1 和 GLIS1 合作刺激 TCF/β-catenin 转录活性，并增强细胞迁移和侵袭。总之，这些结果为 GLIS1 在重新编程基因表达中的作用提供了额外的证据，并提出了 Wnt/β-catenin 通路和上皮-间充质转化的转录调控的分层模型。
