F-box only protein 25-mediated α-actinin 1 upregulation drives ovarian cancer progression via ERK1/2 signaling in tumor cells and macrophage M2 polarization

ACTN1 belongs to the α-actinin family and is considered a tumor-promoting gene in various tumor types; however, the biological function and fundamental molecular mechanisms of ACTN1 in ovarian cancer remain unclear. The HPA and The Cancer Genome Atlas (TCGA) databases were used to compare the expression of ACTN1 in normal ovarian and OC tissues. The Kaplan-Meier Plotter database was used to analyze the relationship between the expression of ACTN1 and the prognosis of ovarian cancer. The TIMER2.0 database was used to analyze the correlation between the expression of ACTN1 and macrophages. CCK-8, colony formation, and Transwell assays as well as flow cytometry were used to determine the biological properties of the cells. Protein expression was assessed by immunohistochemistry, immunofluorescence, and western blot analysis. A co-culture experiment was used to analyze the effect of ovarian cancer cells on the polarization of macrophages. Co-immunoprecipitation was performed to validate the interaction between FBXO25 and ACTN1. ACTN1 was highly expressed in OC tissues and cell lines. Downregulation of ACTN1 attenuated the proliferation, migration, and invasion of OC cells, promoted apoptosis and reduced the aggregation of M2 macrophages and the expression of CD163. The opposite effect was observed following the upregulation of ACTN1. Mechanistically, ACTN1 knockdown reduced ERK1/2 phosphorylation and inhibited epithelial-mesenchymal transition (EMT), whereas its overexpression resulted in the opposite effect. The ERK1/2 inhibitor LY3214996 partially reversed cell proliferation, migration, and M2 polarization of macrophages promoted by ACTN1 overexpression. Moreover, FBXO25, which is upstream of ACTN1 and interacts with it. FBXO25 upregulation partially reversed cell proliferation and migration inhibited by ACTN1 knockdown. Upregulation of ACTN1 by FBXO25 promotes the progression of ovarian cancer by activating the ERK1/2 signaling pathway and M2 polarization of macrophages. The FBXO25/ACTN1/ERK1/2 axis and M2 macrophages may represent promising targets for developing ovarian cancer treatments.