Excessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression

作者：Jialiang Zhang, Ruihong Bai, Mei Li, Huilin Ye, Chen Wu, Chengfeng Wang, Shengping Li, Liping Tan, Dongmei Mai, Guolin Li, Ling Pan, Yanfen Zheng, Jiachun Su, Ying Ye, Zhiqiang Fu, Shangyou Zheng, Zhixiang Zuo, Zexian Liu, Qi Zhao, Xu Che, Dan Xie, Wei‐Hua Jia, Mu‐Sheng Zeng, Wen Tan, Rufu Chen, Rui‐Hua Xu, Jian Zheng, Dongxin Lin · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-09712-x · 被引用次数：405 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、MicroRNA in disease regulation

Abstract N6-methyladenosine (m6A) modification is an important mechanism in miRNA processing and maturation, but the role of its aberrant regulation in human diseases remained unclear. Here, we demonstrate that oncogenic primary microRNA-25 (miR-25) in pancreatic duct epithelial cells can be excessively maturated by cigarette smoke condensate (CSC) via enhanced m6A modification that is mediated by NF-κB associated protein (NKAP). This modification is catalyzed by overexpressed methyltransferase-like 3 (METTL3) due to hypomethylation of theMETTL3promoter also caused by CSC. Mature miR-25, miR-25-3p, suppresses PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2), resulting in the activation of oncogenic AKT-p70S6K signaling, which provokes malignant phenotypes of pancreatic cancer cells. High levels of miR-25-3p are detected in smokers and in pancreatic cancers tissues that are correlated with poor prognosis of pancreatic cancer patients. These results collectively indicate that cigarette smoke-induced miR-25-3p excessive maturation via m6A modification promotes the development and progression of pancreatic cancer.