Abstract
Nerve Growth Factor (NGF) and its high-affinity receptor tropomyosin receptor kinase A (TRKA) increase their expression during the progression of epithelial ovarian cancer (EOC), promoting cell proliferation and angiogenesis through several oncogenic proteins, such as c-MYC and vascular endothelial growth factor (VEGF). The expression of these proteins is controlled by microRNAs (miRs), such as miR-145, whose dysregulation has been related to cancer. The aims of this work were to evaluate in EOC cells whether NGF/TRKA decreases miR-145 levels, and the effect of miR-145 upregulation. The levels of miR-145-5p were assessed by qPCR in ovarian biopsies and ovarian cell lines (human ovarian surface epithelial cells (HOSE), A2780 and SKOV3) stimulated with NGF. Overexpression of miR-145 in ovarian cells was used to evaluate cell proliferation, migration, invasion, c-MYC and VEGF protein levels, as well as tumor formation and metastasis in vivo. In EOC samples, miR-145-5p levels were lower than in epithelial ovarian tumors. Overexpression of miR-145 decreased cell proliferation, migration and invasion of EOC cells, changes that were concomitant with the decrease in c-MYC and VEGF protein levels. We observed decreased tumor formation and suppressed metastasis behavior in mice injected with EOC cells that overexpressed miR-145. As expected, ovarian cell lines stimulated with NGF diminished miR-145-5p transcription and abundance. These results suggest that the tumoral effects of NGF/TRKA depend on the regulation of miR-145-5p levels in EOC cells, and that its upregulation could be used as a possible therapeutic strategy for EOC.
Highlights
Among the malignancies of the female reproductive system, epithelial ovarian cancer (EOC) is the leading cause of death [1,2,3]
Since nerve growth factor (NGF)/tropomyosin receptor kinase A (TRKA) has an important role in EOC and can regulate the expression of many oncogenic proteins, including c-MYC and vascular endothelial growth factor (VEGF), the purpose of this study was to evaluate whether NGF/TRKA modulates miR-145 levels in EOC cells
We described for the first time, the relationship between NGF/TRKA and miR-145 in the context of cancer, contributing to clarify an additional pro-tumoral mechanisms of NGF/TRKA in EOC cells, which involves miR-145 regulation
Summary
Among the malignancies of the female reproductive system, epithelial ovarian cancer (EOC) is the leading cause of death [1,2,3]. NGF enhances proliferation of EOC cells due to increased levels of the c-MYC transcription factor [12], which regulates the expression of cyclins and many oncogenic proteins related to the cell cycle and cell death [13]. One of the most studied angiogenic factors in ovarian cancer is vascular endothelial growth factor (VEGF), whose expression is increased by NGF/TRKA in EOC cells [9,15]. Several studies have shown that ovarian cancer cells can upregulate most oncogenic proteins by altering miR levels [20,21]. Since NGF/TRKA has an important role in EOC and can regulate the expression of many oncogenic proteins, including c-MYC and VEGF, the purpose of this study was to evaluate whether NGF/TRKA modulates miR-145 levels in EOC cells. These results suggest that, at least in part, proliferative and angiogenic mechanisms of NGF are dependent on miR-145 regulation in EOC cells and that miR-145 up-regulation could be considered as a possible therapeutic strategy in EOC
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