Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1

作者：Huang, Jiayuan; Chen, Yitian; Li, Junyang; Zhang, Kai; Chen, Jing; Chen, Dongqin; Feng, Bing; Song, Haizhu; Feng, Jifeng^*; Wang, Rui^*; Chen, Longbang^*

来源：Molecular Therapy - Nucleic Acids, 2016, 5: e375.

DOI：10.1038/mtna.2016.82

• activator protein-1
• chemoresistance
• lung adenocarcinoma
• microRNA
• notch signaling pathway

We previously demonstrated that expression of Notch-1 is associated with poor prognosis in lung adenocarcinoma (LAD) patients. The aim of this study is to reveal whether Notch-1 was associated with Taxanes-resistant LAD and, the underlying mechanisms. We collected 39 patients of advanced LAD treated with Taxanes and found that positive Notch-1 expression is closely related to LAD lymph node metastasis, recurrence and poorer prognosis, and Notch-1 acts as an independent poor prognostic factor in LAD by multivariate analysis with Cox regression model. Then, by using the Docetaxel (DTX)-resistant LAD cell lines that we established previously, we found that Notch-1 contributes to resistance of LAD cells to DTX in vitro, and inhibition of Notch-1 sensitizes LAD to DTX in vivo. We further demonstrated that Notch-1 mediates chemoresistance response and strengthens proliferation capacity in LAD cells partially through negative regulation of miR-451 by transcription factor AP-1. Moreover, we found that MDR-1 is a direct target of miR-451 and influences chemoresistance of LAD cells. Taken together, our data revealed a novel Notch-1/AP-1/miR-451/MDR-1 signaling axis, and suggested a new therapeutic strategy of combining DTX with Notch inhibitors to treat DTX-resistant LAD.

• 出版日期2016-10-11
• 单位江苏省肿瘤防治研究所; 南京大学; 南京医科大学