FBXW7 inhibits invasion, migration and angiogenesis in ovarian cancer cells by suppressing VEGF expression through inactivation of β‑catenin signaling

Abstract

F-box and WD repeat domain containing 7 (FBXW7) is a tumor suppressor gene frequently inactivated in several human malignancies. The present study aimed to investigate the role of FBXW7 in the invasion, migration and angiogenesis of ovarian cancer (OC) cells, and to identify its potential molecular mechanisms. First, the expression levels of FBXW7 and vascular endothelial growth factor (VEGF) were detected in several human OC cell lines using western blotting. Subsequently, FBXW7 was overexpressed to determine VEGF expression in SKOV3 cells. Transwell, wound healing and tube formation assays were performed following transfection with FBXW7 and VEGF overexpression plasmids to assess invasion, migration and angiogenesis in SKOV3 cells, respectively. Western blot analysis was performed to detect the expression levels of epithelial-to-mesenchymal transition and angiogenesis-associated proteins. In addition, the expression levels of β-catenin and c-Myc were assessed, and lithium chloride (LiCl), an agonist of β-catenin signaling, was used to elucidate the molecular mechanisms by which FBXW7 mediates its antitumor activity in OC. The results demonstrated that FBXW7 expression was markedly downregulated, whilst VEGF expression was markedly upregulated in OC cell lines compared with that in normal ovarian cells. Overexpression of FBXW7 significantly decreased VEGF expression in SKOV3 cells. Notably, overexpression of VEGF reversed the inhibitory effects of FBXW7 overexpression on the invasion, migration and angiogenesis of OC cells, accompanied by upregulated expression levels of N-cadherin, slug, CD31, VEGF receptor 1 (VEGFR1) and VEGFR2, and downregulated expression levels of E-cadherin. Furthermore, overexpression of FBXW7 markedly suppressed β-catenin and c-Myc expression, whereas the decreased expression levels of VEGF, VEGFR1 and VEGFR2 following overexpression of FBXW7 were increased after treatment of SKOV3 cells with LiCl. Overall, the results of the present study suggested that FBXW7 inhibited invasion, migration and angiogenesis of OC cells by suppressing VEGF expression through inactivation of β-catenin signaling. Thus, FBXW7 may be used as a novel therapeutic target for the treatment of OC.

FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies

“…miR-144, enriched in tumor-derived extracellular vesicles (EVs) from nasopharyngeal carcinoma (NPC), is demonstrated in vitro and in vivo to promote angiogenesis by downregulating FBXW7 and promoting HIF-1α-induced VEGF-A expression ( 94 ). Notably, FBXW7 can inactivate β-catenin pathway to influence the expression of VEGF-A, ultimately suppressing angiogenesis of ovarian cancer cells ( 95 ).…”

Fbxw7 suppresses carcinogenesis and stemness in triple-negative breast cancer through CHD4 degradation and Wnt/β-catenin pathway inhibition

“…Nuclear β-catenin accumulation is a hallmark of Wnt/β-catenin pathway activation. On the other hand, some studies have demonstrated that FBXW7 can directly ubiquitinate and degrade β-catenin to decrease the activity of the Wnt pathway [ 28 ]. Moreover, our study confirmed that activating or inhibiting the Wnt pathway can inhibit the effects of FBXW7 and CHD4 on the proportion of BCSCs in TNBC cells.…”

Circular RNA circ-BNC2 (hsa_circ_0008732) inhibits the progression of ovarian cancer through microRNA-223-3p/ FBXW7 axis

“…FBXW7 can affect the multiplication and apoptosis of colorectal cancer cells through Notch and Akt/mTOR signaling pathways [ 40 ]. Another study reports that FBXW7 restrains the invasion and migration of OC cells [ 41 ]. The present study proved that FBXW7 expression was declined in OC tissues.…”