miR-494-3p/G6PC/FOXO1 signaling axis drives autophagy-mediated breast cancer progression and predicts poor prognosis

The role of the glucose-6-phosphatase catalytic subunit (G6PC) in breast cancer (BC) remains poorly understood. In this study, we aimed to investigate the expression and prognosis of G6PC in BC and to elucidate the molecular mechanisms by which G6PC regulates the malignant progression of BC. G6PC was markedly upregulated in BC tissues and cells, and elevated G6PC expression was associated with poor patient prognosis. Functional assays showed that G6PC promoted BC cell proliferation, migration, invasion, epithelial-mesenchymal transition, and cell cycle progression, while enhancing autophagy. G6PC accelerates tumor growth and lung metastasis in vivo. Mechanistically, miR-494-3p was found to directly target G6PC and was downregulated in BC; the loss of miR-494-3p led to the upregulation of G6PC expression. Further analyses showed that G6PC interacts with FOXO1 to regulate autophagy, and rescue experiments demonstrated that the miR-494-3p/G6PC/FOXO1 axis is essential for the pro-malignant effects of G6PC in BC. Collectively, these findings identified G6PC as an adverse prognostic factor and uncovered a novel miR-494-3p/G6PC/FOXO1 signaling axis that drives BC progression by modulating autophagy, highlighting a potential target for therapeutic intervention.