ArticleJournal of gastrointestinal oncology2021
Hypoxia promotes pancreatic cancer cell migration, invasion, and epithelial-mesenchymal transition via modulating the FOXO3a/DUSP6/ERK axis.
Article in Journal of gastrointestinal oncology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 10 citations in OpenAlex.
- Environmental exposure to perfluorooctane sulfonate and its role in esophageal cancer progression: a comprehensive bioinformatics and experimental study.Scientific reports · 2025Article
- Catalase-Knockout Complements the Radio-Sensitization Effect of Titanium Peroxide Nanoparticles on Pancreatic Cancer Cells.Molecules (Basel, Switzerland) · 2025Article
- Article
- Pathophysiological Implications of Protein Lactylation in Pancreatic Epithelial Tumors.Acta histochemica et cytochemica · 2024Article
- Hedgehog signaling and the glioma-associated oncogene in cancer radioresistance.Frontiers in cell and developmental biology · 2023Review
- FOXO3a‑modulated DEPDC1 promotes malignant progression of nephroblastoma via the Wnt/β‑catenin signaling pathway.Molecular medicine reports · 2022Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPancreatic 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.
methodsMTT 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.
resultsOur 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.
conclusionsTaken 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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