miR-629-3p may serve as a novel biomarker and potential therapeutic target for lung metastases of triple-negative breast cancer.
miR-629-3p may serve as a novel biomarker and potential therapeutic target for lung metastases of triple-negative breast cancer.
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miR-629-3p可能作为三阴性乳腺癌肺转移的新型生物标志物和潜在治疗靶点
DOI：
10.1186/s13058-017-0865-y
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发表时间：
2017-06-19
期刊：
影响因子：
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通讯作者：
Xie X
中科院分区：
文献类型：
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作者：
Wang J;Song C;Tang H;Zhang C;Tang J;Li X;Chen B;Xie X
不同的乳腺癌亚型对转移部位表现出不同的向性。值得注意的是，肺是三阴性乳腺癌（TNBC）中首次远处复发的最常见部位。识别新的肺转移生物标志物对于改善TNBC的结果具有重要意义。在这项研究中，我们试图确定一个基于microRNA（miRNA）的生物标志物和TNBC肺转移的治疗靶点。本研究共招募了669例无新发IV期TNBC的患者。在发现队列中进行miRNA谱分析。分别在训练和验证队列中评估候选miRNA的诊断准确性和预后价值。通过生物信息学分析以及通过进行体外和体内测定进一步评估候选miRNA的生物学功能以及潜在靶点。在发现集中，我们发现miR-629- 3 p在肺转移患者的转移灶（倍数变化144.16，P < 0.0001）和原发性肿瘤（倍数变化74.37，P = 0.004）中特异性上调。在训练集中，ROC曲线显示miR-629- 3 p在区分肺转移患者和无复发患者方面具有较高的诊断准确性（AUC 0.865，95%CI 0.800-0.930，P < 0.0001）。虽然miR-629- 3 p在验证集中预测了较差的总生存期和无病生存期，但在多变量分析后未能显示出显著性。值得注意的是，logistic回归分析证实miR-629- 3 p是肺转移的独立危险因素（OR 4.1，95%CI 2.5-6.6，P < 0.001）。miR-629- 3 p的抑制显著减弱了TNBC细胞的活力和迁移，并且其显著抑制了体内肺转移。此外，我们确定了白血病抑制因子受体（LIFR），一个众所周知的转移抑制基因，是miR-629- 3 p的直接靶点。miR-629- 3 p可能作为一种新的生物标志物和潜在的治疗靶点，用于通过LIFR介导的TNBC肺转移。本文的在线版本（doi：10.1186/s13058-017-0865-y）包含补充材料，可供授权用户使用。
Different breast cancer subtypes show distinct tropisms for sites of metastasis. Notably, the lung is the most common site for the first distant recurrence in triple-negative breast cancer (TNBC). The identification of novel biomarkers for lung metastasis is of great importance to improving the outcome of TNBC. In this study, we sought to identify a microRNA (miRNA)-based biomarker and therapeutic target for lung metastasis of TNBC. A total of 669 patients without de novo stage IV TNBC were recruited for this study. miRNA profiling was conducted in the discovery cohort. Diagnostic accuracy and prognostic values of candidate miRNAs were evaluated in the training and validation cohorts, respectively. The biological functions of candidate miRNAs, as well as potential targets, were further evaluated through bioinformatic analysis as well as by performing in vitro and in vivo assays. In the discovery set, we found that miR-629-3p was specifically upregulated in both metastatic foci (fold change 144.16, P < 0.0001) and primary tumors (fold change 74.37, P = 0.004) in patients with lung metastases. In the training set, the ROC curve showed that miR-629-3p yielded high diagnostic accuracy in discriminating patients with lung metastasis from patients without recurrence (AUC 0.865, 95% CI 0.800–0.930, P < 0.0001). Although miR-629-3p predicted poor overall survival and disease-free survival in the validation set, it failed to show significance after multivariate analysis. Notably, logistic regression analyses confirmed that miR-629-3p was an independent risk factor for lung metastasis (OR 4.1, 95% CI 2.5–6.6, P < 0.001). Inhibition of miR-629-3p drastically attenuated the viability and migration of TNBC cells, and it markedly suppressed lung metastasis in vivo. Furthermore, we identified the leukemia inhibitory factor receptor (LIFR), a well-known metastatic suppressive gene, to be a direct target of miR-629-3p. miR-629-3p may serve as a novel biomarker and potential therapeutic target for lung metastases of TNBC mediated via LIFR. The online version of this article (doi:10.1186/s13058-017-0865-y) contains supplementary material, which is available to authorized users.