EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AND PROSTAGLANDIN E2 (PGE2): A LINK BETWEEN INFLAMMATION AND CERVICAL CANCER

INTRODUCTION AND OBJECTIVES: Cervical cancer (CC) is the fourth most common tumor in women worldwide. Cisplatin-based chemotherapy is broadly used, yet survival rates remain poor, needing new therapeutic strategies. The epidermal growth factor receptor (EGFR) is highly expressed in solid tumors, being associated with different cellular functions. Previous research showed that EGFR induces cyclooxygenase-2 (COX-2) expression in CC, resulting in prostaglandin E2 (PGE2) production. Cyclooxygenases have two isoforms: COX-1, constitutively expressed in different tissues, while COX-2 is induced in pathological conditions. Studies suggest that PGE2 transactivates EGFR in some models. This work investigated the crosstalk between EGFR and PGE2 signaling pathways in CC and its pro-tumor effects. MATERIAL AND METHODS: EGFR, COX-1, COX-2, and mPGES-1's roles in CC gene expression were evaluated using The Cancer Genome Atlas (TCGA). In vitro experiments used aggressive (HeLa and CASKI) and non-aggressive (C33A) cell lines. Panitumumab inhibited EGFR, and aspirin inhibited COX-1 and -2. Cell migration was evaluated using the Boyden chamber. MTT and clonogenic assays determined cell viability and clonogenicity, respectively. Western Blot analyzed protein expression/phosphorylation. PGE2 was measured in the supernatants of the cell lines using an ELISA kit for human PGE2. RESULTS AND CONCLUSION: TCGA analysis revealed a positive correlation between EGFR and PGE2 biosynthesis pathway genes. Also, CC patients showed decreased overall survival upon overexpression of EGFR or COX-2. In vitro, CASKI and HeLa cells were cisplatin-resistant, while C33A was sensitive. CASKI cells expressed the highest basal levels of EGFR, while HeLa showed elevated COX-2 and mPGES-1 expression. The HeLa cell line showed higher COX-2 expression during the EGF activation kinetics, which was reversed with EGFR inhibition, in protein expression and in the supernatant dosage. PGE2 activated the ERK/MAPK signaling, increasing CC cell motility. The association of panitumumab with aspirin decreased CC cell viability and colony formation. Combination of panitumumab with aspirin-sensitized CASKI cells to cisplatin chemotherapy. We conclude that EGFR-PGE2 pathway interaction links inflammation and oncogenic signaling, promoting aggressive CC behavior.