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首页> 美国卫生研究院文献>Oncotarget >Positive crosstalk between EGFR and the TF-PAR2 pathway mediates resistance to cisplatin and poor survival in cervical cancer
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Positive crosstalk between EGFR and the TF-PAR2 pathway mediates resistance to cisplatin and poor survival in cervical cancer

机译：EGFR和TF-PAR2通路之间的正串扰介导了对顺铂的耐药性和宫颈癌的不良生存

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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.
机译：基于顺铂的化学放射疗法是宫颈癌的标准治疗方法，但是需要化学增敏策略来提高患者的生存率。 EGFR（表皮生长因子受体）是在子宫颈癌中过表达的癌基因，与化学抗性有关。最近的研究表明，EGFR上调了凝血级联反应的多个元素，包括组织因子（TF）和蛋白酶激活受体（PAR）1和2。此外，包括PARs在内的许多G蛋白偶联受体也参与了EGFR反式激活。然而，凝血蛋白在宫颈癌进展中的作用尚未得到充分研究。在这里，我们采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PAR2在化学抗性中的作用。 SLIGKL-NH2肽（PAR2-AP）和凝血因子VIIa（FVIIa）被用作PAR2激动剂，而西妥昔单抗则被用于抑制EGFR。更具攻击性的细胞系CASKI显示的EGFR，TF和PAR2的表达水平高于C33A。 PAR2激活了EGFR，从而进一步上调了环氧合酶2（COX2）的表达。 PAR2-AP通过EGFR和COX2依赖性机制减少顺铂诱导的细胞凋亡。此外，用EGF处理CASKI细胞可上调TF表达，而用西妥昔单抗治疗可降低TF蛋白水平。来自309个TCGA样品的RNA-seq数据显示，EGFR和TF表达之间有很强的正相关性（P = 0.0003）。另外，子宫颈癌患者中EGFR，PAR2或COX2表达的增加与总体生存期差有关。两者合计，我们的结果表明EGFR和COX2是TF / FVIIa / PAR2信号传导途径的效应物，促进了化学抗性。

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