Pathology Division, Research Center for Innovative Oncology, Chiba, Japan.
Biochem Biophys Res Commun. 2012 Jan 20;417(3):1074-9. doi: 10.1016/j.bbrc.2011.12.099. Epub 2011 Dec 26.
The neoplastic transformation by mutant RAS is thought to require remodeling of expression of an entire set of genes. However, the underlying mechanism for initiation of gene expression remodeling in tumorigenesis remains elusive. This study was aimed to define the oncogenic role of EZH2, a histone modifier protein that is induced by oncogenic mutant RAS, using pancreatic cancers of transgenic rats exogenously expressing human mutant RAS. Immunohistochemical observation of preneoplastic or cancerous lesions in the animal model suggested that upregulation of Ezh2 protein is an initiating event in pancreatic carcinogenesis. MEK-inhibition or Elk-1-knockdown downregulated EZH2, and MEK-inhibition or EZH2-knockdown restored expression of a tumor suppressor, RUNX3 in human and rat pancreatic cancer cells activated by the oncogenic RAS. Furthermore, Elk-1- or EZH2-knockdown inhibited growth of the cancer cells. These results strongly suggested that the oncogenic RAS upregulates EZH2 through MEK-ERK signaling, resulted in downregulation of tumor suppressors including RUNX3 in pancreatic carcinogenesis.
突变型 RAS 的肿瘤转化被认为需要重塑一整套基因的表达。然而，肿瘤发生中基因表达重塑起始的潜在机制仍难以捉摸。本研究旨在使用外源性表达人突变型 RAS 的转基因大鼠的胰腺癌来定义组蛋白修饰蛋白 EZH2 的致癌作用，该蛋白被致癌性突变型 RAS 诱导。在动物模型中对癌前或癌性病变的免疫组织化学观察表明，Ezh2 蛋白的上调是胰腺发生癌变的起始事件。MEK 抑制或 Elk-1 敲低下调 EZH2，而 MEK 抑制或 EZH2 敲低恢复了由致癌性 RAS 激活的人源和大鼠胰腺癌细胞中肿瘤抑制因子 RUNX3 的表达。此外，Elk-1 或 EZH2 敲低抑制了癌细胞的生长。这些结果强烈表明，致癌性 RAS 通过 MEK-ERK 信号通路上调 EZH2，导致包括 RUNX3 在内的肿瘤抑制因子在胰腺癌变中下调。
