VEGFR3 suppression through miR‐1236 inhibits proliferation and induces apoptosis in ovarian cancer via ERK1/2 and AKT signaling pathways

Abstract

Vascular endothelial growth factor receptor 3 (VEGFR3) is expressed in cancer cell lines and exerts a critical role in cancer progression. However, the signaling pathways of VEGFR3 in ovarian cancer cell proliferation remain unclear. This study aimed to demonstrate the signaling pathways of VEGFR3 through the upregulated expression of miR-1236 in ovarian cancer cells. We found that the messenger RNA and protein of VEGFR3 were expressed in the ovarian cancer cell lines, but downregulated after microRNA-1236 (miR-1236) transfection. The inhibition of VEGFR3, using miR-1236, significantly reduced cell proliferation, clonogenic survival, migration, and invasion ability in SKOV3 and OVCAR3 cells (p < 0.01). The flow cytometry results indicated that the rate of apoptotic cells in SKOV3 (38.65%) and OVCAR3 (41.95%) cells increased following VEGFR3 inhibition. Moreover, VEGFR3 stimulation (using a specific ligand, VEGF-CS) significantly increased extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation (p < 0.01), whereas VEGFR3 suppression reduced p-ERK1/2 (67.94% in SKOV3 and 93.52% in OVCAR3) and p-AKT (59.56% in SKOV3 and 78.73% in OVCAR3) compared to the VEGF-CS treated group. This finding demonstrated that miR-1236 may act as an endogenous regulator of ERK1/2 and AKT signaling by blocking the upstream regulator of VEGFR3. Overall, we demonstrated the important role of the miR-1236/VEGFR3 axis in ovarian cancer cell proliferation by regulating the ERK1/2 and AKT signaling that might be an effective strategy against ovarian cancer.

Future theranostic strategies: emerging ovarian cancer biomarkers to bridge the gap between diagnosis and treatment

“…Vascular endothelial growth factor receptors (VEGFRs) are a family of transmembrane tyrosine kinase receptors involved in signal transduction pathways to control vascular development of ovarian cancer (Babaei et al, 2023a). VEGFR3 is overexpressed in ovarian cancer cell lines promoting cell growth (Babaei et al, 2023b) and has been identified as a biomarker with potential for the diagnosis and prognosis of ovarian cancer (Klasa-Mazurkiewicz et al, 2011). Moreover, VEGF is a key mediator of angiogenesis and plays a significant role in ovarian cancer development by promoting the recruitment and proliferation of endothelial cells within the tumor (Liang et al, 2015).…”

Deoxynivalenol (DON)-Triggered Dual-Color Composite Probe Based on Gold Nanoclusters for Simultaneous Imaging of DON and miR-34a in Living Cells

“…miRNAs, 18–23 nucleotides in length, are a class of endogenous and noncoding RNA molecules, playing vital roles in regulating cell proliferation, differentiation, apoptosis, and other biological processes . Traditional miRNA detection methods, including northern blotting, microarray method, and RT-qPCR, − are mostly extracting miRNA by lysing cells followed by extracellular detection, which generally suffer from the shortcomings of cumbersome, time-consuming, and inefficient operation, easily resulting in loss of targets during a series of operations .…”