Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1.
Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1.
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Notch-1 通过 AP-1/microRNA-451 介导的 MDR-1 调节赋予肺腺癌对紫杉烷类化学耐药性
DOI：
10.1038/mtna.2016.82
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发表时间：
2016-10-11
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影响因子：
--
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我们先前已经证明Notch-1的表达与肺腺癌(LAD)患者的预后不良有关。本研究的目的是揭示Notch-1是否与紫杉烷类药物耐药的LAD相关，以及其潜在的机制。我们收集了39例接受紫杉烷类药物治疗的晚期LAD患者，发现Notch-1阳性表达与LAD的淋巴转移、复发和预后不良密切相关，多因素分析显示Notch-1是LAD预后不良的独立因素。然后，利用我们先前建立的多西紫杉醇(DTX)耐药的LAD细胞系，我们发现Notch-1在体外有助于LAD细胞对DTX的耐药，在体内抑制Notch-1使LAD对DTX增敏。我们进一步证明了Notch-1通过转录因子AP-1对miR-451的负调控部分地介导了LAD细胞的化疗耐药反应并增强了细胞的增殖能力。此外，我们发现mdr-1是miR-451的直接靶点，并影响LAD细胞的化疗耐药性。综上所述，我们的数据揭示了一个新的Notch-1/AP-1/miR-451/MDR-1信号轴，并建议了DTX与Notch抑制剂联合治疗DTX耐药LAD的新策略。
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.
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