Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, 438 Jiefang Road, Zhenjiang, 212000, China.
Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, 438 Jiefang Road, Zhenjiang, 212000, China; Department of Gastroenterology, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, 201600, China.
Exp Cell Res. 2020 Aug 1;393(1):112091. doi: 10.1016/j.yexcr.2020.112091. Epub 2020 May 16.
Methyl-CpG-binding domain 3 (MBD3), as an induced stem cells reprogramming barrier, has an abnormal expression in various prevalent malignancies. However, in pancreatic cancer cell stemness, the roles of MBD3 remain unclear. In our study, the effects of MBD3 were investigated on the proliferation, stemness and the underlying mechanism in pancreatic cancer cells. Firstly, MBD3 knockdown was proved to promote proliferation and sphere formation of pancreatic cancer cells and tumorigenesis, while MBD3 upregulation inhibited the above results. Also, MBD3 downregulation notably increased stemness markers level of OCT4, NANOG and SOX2, and MBD3 upregulation resulted in the opposite effects. Mechanically, it was found that MBD3 involved in activation of Hippo pathway. There was a negative correlation between MBD3 and YAP expression in TCGA database. MBD3 knockdown improved YAP expression, and promoted YAP nuclear translocation increased TEAD luciferase activity, while MBD3 overexpression reversed the above results. Further evidence revealed that YAP could bind to MBD3, and decreased MBD3 expression. Collectively, MBD3 bound to YAP to significantly inhibit proliferation and weaken stemness maintenance in pancreatic cancer cells, as well as reduce tumorigenesis via Hippo signaling. Thus, MBD3 may serve as a potential molecular biomarker for exploring new therapeutic strategies to treat pancreatic cancer.
甲基化 CpG 结合域 3（MBD3）作为一种诱导干细胞重编程的障碍，在各种常见恶性肿瘤中存在异常表达。然而，在胰腺癌干细胞干性中，MBD3 的作用尚不清楚。在我们的研究中，研究了 MBD3 对胰腺癌细胞增殖、干性及其潜在机制的影响。首先，证实 MBD3 敲低可促进胰腺癌细胞的增殖和球体形成以及肿瘤发生，而 MBD3 上调则抑制了上述结果。此外，MBD3 下调显著增加了 OCT4、NANOG 和 SOX2 的干性标志物水平，而 MBD3 上调则产生相反的效果。机制上，发现 MBD3 参与 Hippo 通路的激活。TCGA 数据库中 MBD3 和 YAP 的表达呈负相关。MBD3 敲低可改善 YAP 表达，并促进 YAP 核转位增加 TEAD 荧光素酶活性，而 MBD3 过表达则逆转了上述结果。进一步的证据表明，YAP 可以与 MBD3 结合，从而降低 MBD3 的表达。总之，MBD3 通过 Hippo 信号通路结合 YAP 显著抑制胰腺癌细胞的增殖和减弱干性维持，并降低肿瘤发生。因此，MBD3 可能作为探索治疗胰腺癌新治疗策略的潜在分子标志物。
