三阴性乳腺癌
癌症研究
MAPK/ERK通路
转移
ABCA1
生物
乳腺癌
癌症
内科学
激酶
细胞生物学
医学
生物化学
基因
运输机
作者
Yanzhong Wang,Xi Zhou,Yinjiao Lei,Yong Chu,Xingtong Yu,Qingchao Tong,Tao Zhu,Haitao Yu,Sining Fang,Guoli Li,Linbo Wang,Gavin Y. Wang,Xinyou Xie,Jun Zhang
出处
期刊:Cancer Letters
[Elsevier]
日期:2022-10-01
卷期号:547: 215884-215884
被引量:18
标识
DOI:10.1016/j.canlet.2022.215884
摘要
Elucidating the mechanism for high metastasis capacity of triple negative breast cancers (TNBC) is crucial to improve treatment outcomes of TNBC. We have recently reported that nicotinamide N-methyltransferase (NNMT) is overexpressed in breast cancer, especially in TNBC, and predicts poor survival of patients undergoing chemotherapy. Here, we aimed to determine the function and mechanism of NNMT on metastasis of TNBC. Additionally, analysis of public datasets indicated that NNMT is involved in cholesterol metabolism. In vitro, NNMT overexpression promoted migration and invasion of TNBCs by reducing cholesterol levels in the cytoplasm and cell membrane. Mechanistically, NNMT activated MEK/ERK/c-Jun/ABCA1 pathway by repressing protein phosphatase 2A (PP2A) activity leading to cholesterol efflux and membrane fluidity enhancement, thereby promoting the epithelial-mesenchymal transition (EMT) of TNBCs. In vivo, the metastasis capacity of TNBCs was weakened by targeting NNMT. Collectively, our findings suggest a new molecular mechanism involving NNMT in metastasis and poor survival of TNBC mediated by PP2A and affecting cholesterol metabolism.
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