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Abstract
Pancreatic cancer (PC) is among the most aggressive types of cancer. Hypoxia has been identified as a key risk factor for cancer progression. The forkhead box (FOX) proteins are multidirectional transcriptional factors that are strongly implicated in malignancies. However, whether FOXO3a, a member of the FOX protein family, is involved in the pro-oncogenic functions of hypoxia in PC has remained largely unelucidated. In this study, we attempted to clarify the role of FOXO3a in metastasis under hypoxic conditions and its underlying mechanism. MTT and flow cytometry assays were performed to detect the cell proliferation and cell cycle distribution respectively. Transwell assays were used to determine the potential of cell migration and invasion. qPCR and western blot assays were used to assess the expression of mRNA and protein. Immunofluorescence assay was performed to evaluate the cellular localization of FOXO3a. FOXO3a overexpression plasmid was constructed to perform the rescue experiment. Our data indicated that PANC-1 and SW1990 cells represented enhanced cell migration and invasion abilities under hypoxia, while no statistical differences in cell proliferation and cell cycle distribution were observed. Hypoxia upregulated the messenger RNA (mRNA) and protein expressions of HIF-1α, FOXO3a, and the key epithelial-mesenchymal transition (EMT)-related (EMT) molecules N-cadherin and vimentin, as well as the phosphorylation of FOXO3a. Interestingly, hypoxia promoted the extranuclear localization of FOXO3a. Overexpression of FOXO3a not only significantly decreased the invasion, migration, and EMT of PC cell lines, but also reversed hypoxia-induced extranuclear localization. Finally, FOXO3a might act as a tumor suppressor in PC by inhibiting the ERK signaling pathway by inducing DUSP6 expression, and the ERK activator fisetin could effectively attenuate the inhibitory role of FOXO3a on ERK. Taken together, our results identified that hypoxia-induced extranuclear localization of FOXO3a promoted cell migration and invasion of human PC by modulating the DUSP6/ERK pathway.
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