Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Yushima Bunkyo-ku, Tokyo, Japan.
Oncogene. 2012 Apr 12;31(15):1963-74. doi: 10.1038/onc.2011.373. Epub 2011 Aug 29.
The epithelial-mesenchymal transition (EMT) has a crucial role in normal and disease processes including tumor progression. In this study, we first classified epithelial-like and mesenchymal-like oral squamous cell carcinoma (OSCC) cell lines based on expression profiles of typical EMT-related genes using a panel of 18 OSCC cell lines. Then, we performed methylation-based and expression-based analyses of components of the Wnt signaling pathway, and identified WNT7A and WNT10A as genes silenced by mesenchymal-specific DNA hypermethylation in OSCCs. A significant association was revealed between some clinicopathological findings and the DNA methylation status of WNT7A (normal vs tumor, P=0.007; T1-2 vs T3-4, P=0.040; I-III vs IV, P=0.016) and WNT10A (N0-N1 vs N2-N3, P=0.046) in the advanced stages of OSCC. Moreover, we found that E-cadherin expression in cancer cells may be positively regulated by WNT7A, whose expression is negatively regulated by mesenchymal-specific DNA hypermethylation or ZEB1 in mesenchymal-like OSCC cells. Our findings indicate that epithelial-specific gene silencing through mesenchymal-specific DNA hypermethylation may stabilize the phenotypic plasticity of cancer cells during EMT/MET.
上皮-间充质转化 (EMT) 在正常和疾病过程中起着至关重要的作用，包括肿瘤进展。在这项研究中，我们首先根据 18 种口腔鳞状细胞癌 (OSCC) 细胞系的典型 EMT 相关基因表达谱对上皮样和间充质样 OSCC 细胞系进行分类。然后，我们对 Wnt 信号通路的成分进行了基于甲基化和基于表达的分析，并鉴定出 WNT7A 和 WNT10A 是 OSCC 中间充质特异性 DNA 高甲基化沉默的基因。在 OSCC 的晚期阶段，WNT7A（正常 vs 肿瘤，P=0.007；T1-2 vs T3-4，P=0.040；I-III vs IV，P=0.016）和 WNT10A（N0-N1 vs N2-N3，P=0.046）的 DNA 甲基化状态与某些临床病理发现之间存在显著相关性。此外，我们发现，癌症细胞中 E-钙黏蛋白的表达可能受到 WNT7A 的正向调控，而 WNT7A 的表达受到间充质特异性 DNA 高甲基化或间充质样 OSCC 细胞中 ZEB1 的负向调控。我们的研究结果表明，通过间充质特异性 DNA 高甲基化对上皮特异性基因的沉默可能在 EMT/MET 过程中稳定癌细胞的表型可塑性。
