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NGF/TRKA Decrease miR-145-5p Levels in Epithelial Ovarian Cancer Cells
Maritza P Garrido1,2, Ignacio Torres1, Alba Avila3
1Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile.
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.
Insights
Nerve Growth Factor (NGF) signaling in ovarian cancer reduces miR-145 levels, hindering tumor suppression. Restoring miR-145 levels inhibits cancer cell growth, invasion, and metastasis, suggesting a potential therapeutic strategy for epithelial ovarian cancer (EOC).
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Nerve Growth Factor (NGF) and its receptor tropomyosin receptor kinase A (TRKA) are upregulated in epithelial ovarian cancer (EOC).
- NGF/TRKA signaling promotes EOC progression by increasing oncogenic proteins like c-MYC and VEGF.
- MicroRNAs (miRs), such as miR-145, regulate gene expression and are often dysregulated in cancer.
Purpose of the Study:
- To investigate if NGF/TRKA signaling decreases miR-145 levels in EOC cells.
- To determine the effects of miR-145 upregulation on EOC cell behavior and tumor progression.
- To explore the therapeutic potential of miR-145 in EOC.
Main Methods:
- Quantitative PCR (qPCR) to assess miR-145-5p levels in ovarian biopsies and cell lines (HOSE, A2780, SKOV3) stimulated with NGF.
- Overexpression of miR-145 in ovarian cancer cells to evaluate proliferation, migration, and invasion.
- Assessment of c-MYC and VEGF protein levels.
- In vivo studies using mouse models to evaluate tumor formation and metastasis.
Main Results:
- miR-145-5p levels were significantly lower in EOC samples compared to normal ovarian tissue.
- NGF stimulation reduced miR-145-5p transcription and abundance in ovarian cell lines.
- Overexpression of miR-145 inhibited EOC cell proliferation, migration, and invasion.
- miR-145 upregulation led to decreased c-MYC and VEGF protein levels.
- In vivo, miR-145 overexpression suppressed tumor formation and metastasis in mice.
Conclusions:
- NGF/TRKA signaling in EOC is associated with decreased miR-145-5p levels.
- miR-145-5p plays a crucial role in suppressing EOC cell proliferation, invasion, and metastasis.
- Upregulation of miR-145-5p represents a promising therapeutic strategy for epithelial ovarian cancer.
