Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer.
Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer.
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DOI：
10.1158/1078-0432.ccr-16-0709
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发表时间：
2017-01-01
期刊：
影响因子：
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通讯作者：
Fazio VM
中科院分区：
文献类型：
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作者：
De Robertis M;Loiacono L;Fusilli C;Poeta ML;Mazza T;Sanchez M;Marchionni L;Signori E;Lamorte G;Vescovi AL;Garcia-Foncillas J;Fazio VM
EphA 2受体参与与包括EGFR、FAK和VEGF途径在内的其他细胞网络的多种交叉对话，与这些细胞网络协作以刺激细胞迁移、侵袭和转移。结直肠癌（CRC）EphA 2过表达也与细胞的干细胞样性质和肿瘤恶性度相关。我们研究了EphA 2和EGFR通路的分子串扰和microRNA调节。我们还探讨了EphA 2/EGFR通路介导物作为西妥昔单抗在CRC患者中获益的预后因素或预测因子的作用。通过FACS辅助程序在从AOM/DSS小鼠模型的CRC分离的EphA 2 high细胞中进行基因表达分析。通过EphA 2表达对六个独立的患者队列进行分层，以确定EphA 2/EGFR特征的潜在预后作用及其对西妥昔单抗治疗反应的影响。我们确定了一种基因表达模式（EphA 2，Efna 1，EGFR，Ptpn 12，Atf 2），反映了EphA 2和EGFR通路的激活以及mir-26 b和mir-200 a的一致失调。在单因素和多因素分析中，这种模式在I-III期CRC患者中显示出预后意义。在IV期和WT KRAS患者中，EphA 2/Efna 1/EGFR基因表达状态与西妥昔单抗治疗反应不良显著相关。此外，EphA 2和EGFR过表达显示出与西妥昔单抗耐药相关的联合效应，与KRAS突变状态无关。这些结果表明，EphA 2/Efna 1/EGFR基因，与mir-200 a和mir-26 b的可能控制相关，可以作为新的CRC预后生物标志物。此外，EphA 2可能与西妥昔单抗耐药机制有关，而不是KRAS突变。
EphA2 receptor is involved in multiple cross-talks with other cellular networks including EGFR, FAK and VEGF pathways, with which it collaborates to stimulate cell migration, invasion and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular crosstalk and microRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in CRC patients. Gene expression analysis was performed in EphA2high cells isolated from CRC of AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response. We identified a gene expression pattern (EphA2, Efna1, EGFR, Ptpn12, Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such pattern showed prognostic significance in stage I-III CRC patients, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/EGFR gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status. These results suggest that EphA2/Efna1/EGFR genes, linked to a possible control by mir-200a and mir-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations.