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

• Published in: Nature communications Vol. 10; no. 1
• Main Authors: Zhang, Jialiang, Bai, Ruihong, Li, Mei, Ye, Huilin, Wu, Chen, Wang, Chengfeng, Li, Shengping, Tan, Liping, Mai, Dongmei, Li, Guolin, Pan, Ling, Zheng, Yanfen, Su, Jiachun, Ye, Ying, Fu, Zhiqiang, Zheng, Shangyou, Zuo, Zhixiang, Liu, Zexian, Zhao, Qi, Che, Xu, Xie, Dan, Jia, Weihua, Zeng, Mu-Sheng, Tan, Wen, Chen, Rufu, Xu, Rui-Hua, Zheng, Jian, Lin, Dongxin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.04.2019; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/44; 13/89; 38/61; 38/77; 38/88; 38/90; 38/91; 59/5; 631/67/1504/1713; 64/60; 82/29; 82/58; Activation; AKT protein; Cancer; Cigarette smoke; Cigarettes; Epithelial cells; Humanities and Social Sciences; Leucine; Maturation; Methyltransferase; MicroRNAs; miRNA; multidisciplinary; N6-methyladenosine; NF-κB protein; Pancreatic cancer; Phenotypes; Phosphatase; Protein phosphatase; Proteins; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Smoke; Smoking
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09712-x

N 6 -methyladenosine (m 6 A) 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 m 6 A modification that is mediated by NF-κB associated protein (NKAP). This modification is catalyzed by overexpressed methyltransferase-like 3 (METTL3) due to hypomethylation of the METTL3 promoter 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 m 6 A modification promotes the development and progression of pancreatic cancer. Cigarette smoke induces microRNA dysregulation in cancers. Here, the authors show that cigarette smoke promotes the maturation of oncogenic primary miR-25 due to METTL3 hypomethylation, and mature miR-25 suppresses PH domain leucine-rich repeat protein phosphatase 2, resulting in oncogenic AKT activation in pancreatic cancer.