Abstract
Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, β-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.
Highlights
Epithelial ovarian cancer (EOC), the most common subtype of ovarian cancer, is one of the most lethal gynaecological neoplasms in women worldwide, and is characterized by non-specific symptoms and late diagnosis, which result in poor survival rates [1,2,3]
Results from our group showed that nerve growth factor (NGF)/tropomyosin receptor kinase A (TRKA) is highly expressed in EOC cells compared to non-tumoral ovarian cells, which leads to increased NGF/TRKA signalling [4]
Previous results from our group showed that NGF/TRKA increases the proliferation of EOC cells [46] and c-MYC protein levels in EOC explants [7,8]
Summary
Epithelial ovarian cancer (EOC), the most common subtype of ovarian cancer, is one of the most lethal gynaecological neoplasms in women worldwide, and is characterized by non-specific symptoms and late diagnosis, which result in poor survival rates [1,2,3]. Some studies have shown that presence and expression of NGF and its high affinity receptor TRKA increase during EOC progression, and promote tumour cell proliferation and angiogenesis by activation of the phosphoinositide 3-kinases (PI3K)/ Protein kinase B (AKT) and mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinase (ERK) signalling pathways [4,7,8,9]. NGF/TRKA signalling (via PI3K/AKT and MAPK/ERK pathways) increases the expression of oncoproteins such as survivin and β-catenin, in cancer cells [11,12,13,14,15], and these two proteins are upregulated in EOC [16,17]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
