miR-629-3p可能作为三阴性乳腺癌肺转移的一种新型生物标志物和潜在治疗靶点。
miR-629-3p may serve as a novel biomarker and potential therapeutic target for lung metastases of triple-negative breast cancer.
作者信息
Wang Jin, Song Cailu, Tang Hailin, Zhang Chao, Tang Jun, Li Xing, Chen Bo, Xie Xiaoming
机构信息
Department of Breast Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, No.651 Dongfeng East Road, Yuexiu District, Guangzhou, Guangdong, 510060, People's Republic of China.
Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.
出版信息
Breast Cancer Res. 2017 Jun 19;19(1):72. doi: 10.1186/s13058-017-0865-y.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
miR-629-3p may serve as a novel biomarker and potential therapeutic target for lung metastases of TNBC mediated via LIFR.
背景
不同的乳腺癌亚型对转移部位表现出不同的嗜性。值得注意的是，肺是三阴性乳腺癌（TNBC）首次远处复发最常见的部位。鉴定用于肺转移的新型生物标志物对于改善TNBC的预后至关重要。在本研究中，我们试图鉴定一种基于微小RNA（miRNA）的生物标志物和TNBC肺转移的治疗靶点。
方法
本研究共招募了669例无初发性IV期TNBC的患者。在发现队列中进行了miRNA谱分析。分别在训练队列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进行体外和体内试验，进一步评估候选miRNA的生物学功能及其潜在靶点。
结果
在发现集中，我们发现miR-629-3p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）中均特异性上调。在训练集中，ROC曲线显示miR-629-3p在区分有肺转移的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-629-3p在验证集中预测总体生存率和无病生存率较差，但在多变量分析后未显示出显著性。值得注意的是，逻辑回归分析证实miR-629-3p是肺转移的独立危险因素（OR 4.1，95% CI 2.5 - 6.6，P < 0.001）。抑制miR-629-3p可显著减弱TNBC细胞的活力和迁移能力，并在体内明显抑制肺转移。此外，我们确定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-629-3p的直接靶点。
结论
miR-629-3p可能作为TNBC肺转移通过LIFR介导的新型生物标志物和潜在治疗靶点。
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