Signaling Pathways Related to Nerve Growth Factor and miRNAs in Epithelial Ovarian Cancer

Abstract

Epithelial ovarian cancer (EOC) is a disease that causes 140,000 deaths every year. Nerve growth factor (NGF) and its high affinity receptor TRKA play important roles in fol licular maturation, follicle-stimulating hormone (FSH) receptor acquisition and ovu - lation in normal ovary. Also, NGF has many roles in EOC cells: increasing survival, proliferation, cyclooxigenase-2 (COX-2), vascular endothelial growth factor (VEGF) and metalloproteinase ADAM17 expression. Besides, NGF inhibits calreticulin transloca tion from the endoplasmic reticulum to cell surface, possibly diminishing the efficacy of immunogenic therapies in EOC. Additionally, NGF acts as an angiogenic factor by a direct stimulation of migration, differentiation and proliferation of endothelial cells. Among the numerous factors actually described to be important in many types of can -cer, including EOC, are the microRNAs (miRs). Indeed, it has been found that miR-143 is downregulate in EOC, which correlates with an increase of COX-2; concomitantly, NGF increases COX-2 as mentioned. Furthermore, NGF increases miR-222 and its target is the metalloproteinase inhibitor TIMP3, increasing the ADAM17 function. Also, NGF increases cMYC transcription factor in EOC, which decreases miR-23 levels regulating proteins involved in cell cycle and tumor growth. Therefore, NGF/TRKA signaling path ways alter the expression of many proteins and deregulate miRs in EOC, leading to the progression of this cancer.