Department of Pathology, University of Tokyo, Tokyo, Japan.
Department of Molecular Pathology, University of Tokyo, Tokyo, Japan.
Oncogene. 2014 May 8;33(19):2454-63. doi: 10.1038/onc.2013.204. Epub 2013 Jun 10.
Despite frequent KRAS mutation, the early molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) development have not been fully elucidated. By tracking a potential regulator of another feature of PDAC precursors, acquisition of foregut or gastric epithelial gene signature, we herein report that aberrant overexpression of ecotropic viral integration site 1 (EVI1) oncoprotein, which is usually absent in normal pancreatic duct, is a widespread marker across the full spectrum of human PDAC precursors and PDAC. In pancreatic cancer cells, EVI1 depletion caused remarkable inhibition of cell growth and migration, indicating its oncogenic roles. Importantly, we found that EVI1 upregulated KRAS expression through suppression of a potent KRAS suppressor, miR-96, in pancreatic cancer cells. Collectively, the present findings suggest that EVI1 overexpression and KRAS mutation converge on activation of the KRAS pathway in early phases of pancreatic carcinogenesis and propose EVI1 and/or miR-96 as early markers and therapeutic targets in this dismal disease.
尽管 KRAS 经常发生突变，但胰腺导管腺癌 (PDAC) 发展的早期分子机制仍未完全阐明。通过跟踪另一个 PDAC 前体特征的潜在调节剂——获得前肠或胃上皮基因特征，我们在此报告，异常过表达通常不存在于正常胰腺导管中的原癌基因 ecotropic viral integration site 1 (EVI1) 蛋白是人类 PDAC 前体和 PDAC 的全谱广泛标志物。在胰腺癌细胞中，EVI1 缺失导致细胞生长和迁移的显著抑制，表明其具有致癌作用。重要的是，我们发现 EVI1 通过抑制胰腺癌细胞中一种有效的 KRAS 抑制剂 miR-96，上调 KRAS 表达。总之，这些发现表明，EVI1 过表达和 KRAS 突变在胰腺发生的早期阶段集中于 KRAS 通路的激活，并提出 EVI1 和/或 miR-96 作为这种疾病的早期标志物和治疗靶点。
