Positive crosstalk between EGFR and the TF-PAR2 pathway mediates resistance to cisplatin and poor survival in cervical cancer.
Positive crosstalk between EGFR and the TF-PAR2 pathway mediates resistance to cisplatin and poor survival in cervical cancer.
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DOI：
10.18632/oncotarget.25748
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发表时间：
2018-07-17
期刊：
影响因子：
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通讯作者：
Monteiro, Robson Q
中科院分区：
文献类型：
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作者：
Hugo de Almeida, Vitor;Guimaraes, Isabella Dos Santos;Monteiro, Robson Q
顺铂为基础的放化疗是宫颈癌的标准治疗方法，但需要化疗增敏策略来提高患者的生存率。EGFR（表皮生长因子受体）是一种在宫颈癌中过表达的癌基因，与化疗耐药性有关。最近的研究表明，EGFR上调凝血级联反应的多种元素，包括组织因子（TF）和蛋白酶激活受体（PAR）1和2。此外，许多G蛋白偶联受体，包括PAR，已经涉及EGFR反式激活。然而，凝血蛋白在宫颈癌进展中的作用研究甚少。在此，我们使用宫颈癌细胞系和癌症基因组图谱（TCGA）数据库来评估EGFR、TF和PAR 2在化疗耐药性中的作用。SLIGKL-NH 2肽（PAR 2-AP）和凝血因子VIIa（FVIIa）用作PAR 2激动剂，而西妥昔单抗用于抑制EGFR。CASKI细胞系EGFR、TF和PAR 2的表达水平高于C33 A细胞系。PAR 2反式激活EGFR，其进一步上调环氧合酶-2（COX 2）表达。PAR 2-AP通过EGFR和COX 2依赖性机制减少顺铂诱导的细胞凋亡。此外，用EGF处理CASKI细胞上调TF表达，而用西妥昔单抗处理降低TF蛋白水平。来自309个TCGA样本的RNA-seq数据显示EGFR和TF表达之间存在强正相关性（P = 0.0003）。此外，EGFR、PAR 2或COX 2在宫颈癌患者中的表达增加与总生存率差显著相关。综上所述，我们的研究结果表明，EGFR和COX 2是TF/FVIIa/PAR 2信号通路的效应子，促进了化疗耐药性。
Cisplatin-based chemoradiation is the standard treatment for cervical cancer, but chemosensitizing strategies are needed to improve patient survival. EGFR (Epidermal Growth Factor Receptor) is an oncogene overexpressed in cervical cancer that is involved in chemoresistance. Recent studies showed that EGFR upregulates multiple elements of the coagulation cascade, including tissue factor (TF) and the protease-activated receptors (PAR) 1 and 2. Moreover, many G protein-coupled receptors, including PARs, have been implicated in EGFR transactivation. However, the role of coagulation proteins in the progression of cervical cancer has been poorly investigated. Herein we employed cervical cancer cell lines and The Cancer Genome Atlas (TCGA) database to evaluate the role of EGFR, TF and PAR2 in chemoresistance. The SLIGKL-NH2 peptide (PAR2-AP) and coagulation factor VIIa (FVIIa) were used as PAR2 agonists, while cetuximab was used to inhibit EGFR. The more aggressive cell line CASKI showed higher expression levels of EGFR, TF and PAR2 than that of C33A. PAR2 transactivated EGFR, which further upregulated cyclooxygenase-2 (COX2) expression. PAR2-AP decreased cisplatin-induced apoptosis through an EGFR- and COX2-dependent mechanism. Furthermore, treatment of CASKI cells with EGF upregulated TF expression, while treatment with cetuximab decreased the TF protein levels. The RNA-seq data from 309 TCGA samples showed a strong positive correlation between EGFR and TF expression (P = 0.0003). In addition, the increased expression of EGFR, PAR2 or COX2 in cervical cancer patients was significantly correlated with poor overall survival. Taken together, our results suggest that EGFR and COX2 are effectors of the TF/FVIIa/PAR2 signaling pathway, promoting chemoresistance.