Genistin Represses the Proliferation and Angiogenesis While Accelerating the Apoptosis of Glioma Cells by Modulating the FOXC1-Mediated Wnt Signaling Pathway

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Abstract
Background: Glioma is a tumor originating from glial cells and is the most common primary brain tumor. At present, the main treatment methods for glioma include surgical resection and radiotherapy and chemotherapy, but the treatment effect is not very ideal. Genistin (GS) inhibits breast cancer cell growth while promoting apoptosis, but its effect and detailed molecular mechanism on glioma are yet to be defined. In addition, forkhead box C1 (FOXC1) has been found to be involved in the growth, invasion, and angiogenesis processes of glioma cells. Methods: Human glioma cells in the Control, GS-6.25, GS-12.5, and GS25 (GS) groups were treated with 0, 6.25, 12.5, and 25 μM of Genistin, respectively, for 72 hours, and cells in the GS + NC (negative control) and GS + FOXC1 groups were transfected with negative control or forkhead box C1 (FOXC1) overexpression plasmids, respectively, prior to Genistin (25 μM) treatment for 72 hours. Next, the viability, proliferation, apoptosis, and angiogenesis of treated glioma cells were detected using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2′deoxyuridine (EdU) proliferation, flow cytometry, and tube formation assays. Meanwhile, the half-maximal inhibitory concentration (IC50) of Genistin in the treated glioma cells was calculated. Afterwards, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot quantified the levels of FOXC1, Wnt1, Wnt3a, glycogen synthase kinase-3β (GSK3β), and phosphorylated GSK3β (p-GSK3β). Results: Genistin inhibited viability, proliferation, and angiogenesis while promoting the apoptosis of glioma cells (p < 0.05, p < 0.001). Also, Genistin decreased the levels of FOXC1, Wnt1, and Wnt3a while increasing p-GSK3β levels in glioma cells (p < 0.05, p < 0.01, p < 0.001). FOXC1 was up-regulated in glioma cells and tissues, and overexpressed FOXC1 overturned the effects of Genistin on the abovementioned factors in glioma cells (p < 0.05, p < 0.001). Conclusions: Genistin inhibits viability, proliferation, and angiogenesis while accelerating glioma cell apoptosis by modulating the FOXC1-mediated Wnt signaling pathway.

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