CROSSTALK BETWEEN EPIDERMAL GROWTH FACTOR RECECPTOR (EGFR) AND PROSTAGLANDIN E2 (PGE2): A POSSIBLE LINK BETWEEN CERVICAL CANCER AND INFLAMMATION?

INTRODUCTION AND OBJECTIVES: Cervical cancer is the third most common tumor in women in Brazil and the fourth leading cause of cancer death in women around the world. Chemotherapy and radiotherapy are widely used treatments for cervical tumors, however, in recent years survival rates have stabilized, highlighting the need for new therapeutic modalities to treat these patients. The epidermal growth factor receptor (EGFR) is a proto-oncogene highly expressed in cervical cancer. EGFR signaling has associated with different cellular functions such as cell migration, cell death, cell differentiation and angiogenesis. In addition, studies have shown that EGFR induces the expression of the inflammatory enzyme cyclooxygenase-2 (COX-2), whose product is prostaglandin E2 (PGE2) - an agonist for the EP receptors class. Cyclooxygenase enzymes have two isoforms: COX-1, encoded by a gene constitutively expressed in different tissues; and COX-2 is encoded by a gene, whose expression is induced under pathological conditions such as inflammation and cancer. Recent literature data point to a new mechanism of action of EP receptors and other GPCRs, based on EGFR transactivation. Thus, this work aimed to investigate the transactivation of the EGFR signaling pathway by PGE2 in vitro and the pro-tumor effects associated with it. MATERIAL AND METHODS: In this work, we used The Cancer Genome Atlas (TCGA) database to estimate the impact of EGFR, COX-1, COX-2 and mPGES-1 gene expression in the survival rate of patients with cervical tumors. PGE2 was used as an agonist of EP receptors, while panitumumab was used as a pharmacological inhibitor of EGFR activation in CASKI and HeLa cell lines. Cell migration assays were performed using the Boyden chamber. RESULTS AND CONCLUSION: RNAseq analysis of the TCGA database revealed that there is a positive correlation between EGFR expression and genes encoding COX-1, COX-2 and mPGES-1 in 306 cervical tumor samples. Patient survival analyzes showed that EGFR and COX-2 have a negative prognostic value, impacting on a worse overall survival in patients with tumor overexpression of this enzyme. In vitro analyses demonstrated that PGE2 activates the MAPKs (Mitogen-Activated Protein Kinases) pathway in cervical tumor cell lines by an EGFR-dependent mechanism. In the cell migration assay, we observed that PGE2 increases the migratory capacity of these cells, while the pharmacological inhibition of EGFR reverses this phenomenon. Therefore, a better understanding of the crosstalk between the EGFR pathway and the PGE2 biosynthesis pathway can help us understand the biology of cervical tumor cells and reveal new therapeutic targets.