The prognostic value of JUNB-positive CTCs in metastatic breast cancer: from bioinformatics to phenotypic characterization
The prognostic value of JUNB-positive CTCs in metastatic breast cancer: from bioinformatics to phenotypic characterization
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DOI：
10.1186/s13058-019-1166-4
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发表时间：
2019-08-01
影响因子：
7.4
通讯作者：
Georgoulias, Vassilis
中科院分区：
文献类型：
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作者：
Kallergi, Galatea;Tsintari, Vasileia;Georgoulias, Vassilis
背景：循环肿瘤细胞（CTC）是肿瘤转移扩散的重要因素。它们可以提供关于生物学特征和肿瘤异质性的有用信息;然而，由于它们在血流中的数量有限及其间充质特征，它们的检测和表征是困难的。因此，需要新的生物标志物来解决这些问题。方法：生物信息学功能富集分析揭示了一个亚组的24个基因，可能过表达的CTC。在这些基因中，趋化因子受体CXCR 4起着核心作用。在根据CXCR 4相应途径进行优先级排序后，选择五种分子（JUNB、YWHAB、TYROBP、NFYA和PRDX 1）用于生物样品中的进一步分析。使用SKBR 3、MDA-MB 231和MCF 7细胞系以及来自正常（n = 10）献血者的PBMCs作为对照，以定义所有检测分子的表达模式。因此，使用以下抗体组合分析100名先前未经治疗的转移性乳腺癌（mBC）患者（n = 100）：CK（细胞角蛋白）/CXCR 4/JUNB、CK/NFYA/YWHAB（14-3-3）和CK/TYROBP/PRDX 1。结果：CXCR 4在SKBR 3和CTCs中的表达水平依次为SKBR 3>CTCs>Hela> MCF 7> MDA-MB 231。JUNB也在CTC中过表达（SKBR 3> CTC> MCF 7> MDA-MB 231>Hela）。根据每个分子的定义阈值，在90%的血液中可检测到肿瘤细胞的患者中鉴定出CXCR 4阳性CTC。此外，分别有65%、75%、14.3%和12.5%的患者携带JUNB、TYROBP、NFYA和PRDX阳性CTC。相反，没有患者显示YWI-IAB阳性CTC。有趣的是，与患者的血细胞相比，CTC中的JUNB表达在表型上和统计学上增强（p = 0.002），为CTC提供了可能的新生物标志物。此外，患者中JUNB阳性CTC的检测与PFS（p = 0.015）和OS（p = 0.002）较差相关。结论：CXCR 4、JUNB和TYROBP在CTCs中过表达，但只有JUNB的表达与不良预后相关，为消除CTCs提供了新的生物标志物和潜在的治疗靶点。
Background: Circulating tumor cells (CTCs) are important for metastatic dissemination of cancer. They can provide useful information, regarding biological features and tumor heterogeneity; however, their detection and characterization are difficult due to their limited number in the bloodstream and their mesenchymal characteristics. Therefore, new biomarkers are needed to address these questions.Methods: Bioinformatics functional enrichment analysis revealed a subgroup of 24 genes, potentially overexpressed in CTCs. Among these genes, the chemokine receptor CXCR4 plays a central role. After prioritization according to the CXCR4 corresponding pathways, five molecules (JUNB, YWHAB, TYROBP, NFYA, and PRDX1) were selected for further analysis in biological samples. The SKBR3, MDA-MB231, and MCF7 cell lines, as well as PBMCs from normal (n = 10) blood donors, were used as controls to define the expression pattern of all the examined molecules. Consequently, 100 previously untreated metastatic breast cancer (mBC) patients (n = 100) were analyzed using the following combinations of antibodies: CK (cytokeratin)/CXCR4/JUNB, CK/NFYA/YWHAB (14-3-3), and CK/TYROBP/PRDX1. A threshold value for every molecule was considered the mean expression in normal PBMCs.Results: Quantification of CXCR4 revealed overexpression of the receptor in SKBR3 and in CTCs, following the subsequent scale (SKBR3>CTCs>Hela>MCF7>MDA-MB231). JUNB was also overexpressed in CTCs (SKBR3>CTCs>MCF7>MDA-MB231>Hela). According to the defined threshold for each molecule, CXCR4-positive CTCs were identified in 90% of the patients with detectable tumor cells in their blood. In addition, 65%, 75%, 14.3%, and 12.5% of the patients harbored JUNB-, TYROBP-, NFYA-, and PRDX-positive CTCs, respectively. Conversely, none of the patients revealed YWI-IAB-positive CTCs. Interestingly, JUNB expression in CTCs was phenotypically and statistically enhanced compared to patients' blood cells (p = 0.002) providing a possible new biomarker for CTCs. Furthermore, the detection of JUNB-positive CTCs in patients was associated with poorer PFS (p = 0.015) and OS (p = 0.002). Moreover, JUNB staining of 11 primary and 4 metastatic tumors from the same cohort of patients revealed a dramatic increase of JUNB expression in metastasis.Conclusions: CXCR4, JUNB, and TYROBP were overexpressed in CTCs, but only the expression of JUNB was associated with poor prognosis, providing a new biomarker and a potential therapeutic target for the elimination of CTCs.