Abstract
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.
Highlights
Cervical cancer is the fourth most common tumor and the fourth leading cause of cancer death in women worldwide, with 570,000 cases and 311,000 deaths in 2018
To initiate the current study, transcriptome data from cervical cancer patients deposited in The Cancer Genome Atlas (TCGA) were used to observe possible correlations between the mRNA expression levels of Epidermal growth factor receptor (EGFR), cytosolic phospholipase A2 (cPLA2), PAF receptor (PAFR) and the components of the lysophosphatidylcholine acyltransferase (LPCAT) family
Albeit a slight correlation between the expression of EGFR and LPCAT3 was found (Spearman’s r = 0.1160, P = 0.0416, Supplementary Figure 1B), PAFR and LPCAT2 were chosen for the subsequent studies due to the strength of the correlation with EGFR, which suggests a possible mechanism of transcriptional regulation
Summary
Cervical cancer is the fourth most common tumor and the fourth leading cause of cancer death in women worldwide, with 570,000 cases and 311,000 deaths in 2018. Patients with advancedstage tumors have 5-year survival rates lower than 50% [2], and novel therapeutic strategies are needed to improve these women’s prognosis Membrane proteins, such as receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), are critical in the intercellular communication and signal transduction, modulating gene expression and cell responses to the extracellular stimuli. Alterations in these receptors and their regulated signaling pathways are commonly observed in cell transformation and tumor progression, making them useful as biomarkers, prognostic factors, and pharmacological targets [3]. Previous reports demonstrated that EGFR can be transactivated by various agonists unrelated to EGFR ligands, such as GPCR ligands, in models that include cervical cancer cells [9,10,11]
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