Interplay Between EGFR and the Platelet-Activating Factor/PAF Receptor Signaling Axis Mediates Aggressive Behavior of Cervical Cancer.
Interplay Between EGFR and the Platelet-Activating Factor/PAF Receptor Signaling Axis Mediates Aggressive Behavior of Cervical Cancer.
复制标题
DOI：
10.3389/fonc.2020.557280
复制
发表时间：
2020
影响因子：
4.7
通讯作者：
Almeida VH
中科院分区：
文献类型：
--
作者：
Souza JL;Martins-Cardoso K;Guimarães IS;de Melo AC;Lopes AH;Monteiro RQ;Almeida VH
表皮生长因子受体（Epidermal growth factor receptor，EGFR）是一种广泛表达于宫颈肿瘤的酪氨酸激酶受体，与宫颈癌的临床预后密切相关。EGFR可通过多种机制激活，包括通过G蛋白偶联受体（GPCR）的反式激活。研究还表明，血小板活化因子（PAF），一种促炎性磷脂介质，通过调节癌细胞或肿瘤微环境在癌症进展中起重要作用。大多数PAF效应似乎是通过与其受体（PAFR）的相互作用介导的，PAFR是GPCR家族的成员。PAFR-和EGFR-诱发的信号通路有助于肿瘤生物学;然而，它们之间的相互作用在宫颈癌中仍然未被研究。在这项研究中，我们采用癌症基因组图谱（TCGA）和癌细胞系，以评估可能的合作EGFR，PAFR和溶血磷脂酰胆碱酰基转移酶（LPCAT），酶参与PAF的生物合成，在宫颈癌的背景下。306例宫颈癌组织中EGFR × PAFR和EGFR × LPCAT 2的表达呈显著正相关。LPCAT 2表达增加与总生存率低显著相关。EGFR的激活以MAPK依赖的方式上调PAFR和LPCAT 2的表达。同时，PAF显示出能够反式激活EGFR，导致ERK/MAPK激活、环氧化酶-2（考克斯-2）诱导和细胞迁移。PAF-PAFR轴和EGFR之间的正串扰证明了宫颈癌细胞中炎症和生长因子信号传导之间的相关联系。最后，PAFR和EGFR联合靶向治疗比每种单独治疗更严重地损害了侵袭性宫颈癌细胞的克隆形成能力和活力。总的来说，我们提出EGFR、LPCAT 2和PAFR成为宫颈癌治疗的新靶点。
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in cervical tumors, being correlated with adverse clinical outcomes. EGFR may be activated by a diversity of mechanisms, including transactivation by G-protein coupled receptors (GPCRs). Studies have also shown that platelet-activating factor (PAF), a pro-inflammatory phospholipid mediator, plays an important role in the cancer progression either by modulating the cancer cells or the tumor microenvironment. Most of the PAF effects seem to be mediated by the interaction with its receptor (PAFR), a member of the GPCRs family. PAFR- and EGFR-evoked signaling pathways contribute to tumor biology; however, the interplay between them remains uninvestigated in cervical cancer. In this study, we employed The Cancer Genome Atlas (TCGA) and cancer cell lines to evaluate possible cooperation between EGFR, PAFR, and lysophosphatidylcholine acyltransferases (LPCATs), enzymes involved in the PAF biosynthesis, in the context of cervical cancer. It was observed a strong positive correlation between the expression of EGFR × PAFR and EGFR × LPCAT2 in 306 cervical cancer samples. The increased expression of LPCAT2 was significantly correlated with poor overall survival. Activation of EGFR upregulated the expression of PAFR and LPCAT2 in a MAPK-dependent fashion. At the same time, PAF showed the ability to transactivate EGFR leading to ERK/MAPK activation, cyclooxygenase-2 (COX-2) induction, and cell migration. The positive crosstalk between the PAF-PAFR axis and EGFR demonstrates a relevant linkage between inflammatory and growth factor signaling in cervical cancer cells. Finally, combined PAFR and EGFR targeting treatment impaired clonogenic capacity and viability of aggressive cervical cancer cells more strongly than each treatment separately. Collectively, we proposed that EGFR, LPCAT2, and PAFR emerge as novel targets for cervical cancer therapy.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
4.1
作者：
da Silva Junior IA;Stone SC;Rossetti RM;Jancar S;Lepique AP
通讯作者：
Lepique AP
影响因子：
--
作者：
Hugo de Almeida, Vitor;Guimaraes, Isabella Dos Santos;Monteiro, Robson Q
通讯作者：
Monteiro, Robson Q
溶血磷脂酰胆碱酰基转移酶2介导的脂质液滴生产支持结直肠癌的化学耐药性。
影响因子：
16.6
作者：
Cotte AK;Aires V;Fredon M;Limagne E;Derangère V;Thibaudin M;Humblin E;Scagliarini A;de Barros JP;Hillon P;Ghiringhelli F;Delmas D
通讯作者：
Delmas D
DOI：
10.1590/1414-431x20176822
发表时间：
2017-11-13
期刊：
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
影响因子：
--
作者：
de Almeida VH;de Melo AC;Meira DD;Pires AC;Nogueira-Rodrigues A;Pimenta-Inada HK;Alves FG;Moralez G;Thiago LS;Ferreira CG;Sternberg C
通讯作者：
Sternberg C