Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H2O2-induced, ERK-associated up-regulation of HIF-1α and VEGF-A.

Abstract

Several NADPH oxidase family members, including dual oxidase 2 [DUOX2], are expressed in human tumors, particularly gastrointestinal cancers associated with long-standing chronic inflammation. We found previously that exposure of pancreatic ductal adenocarcinoma cells to the pro-inflammatory cytokine IFN-γ increased DUOX2 expression (but not other NADPH oxidases) leading to long-lived H2O2 production. To elucidate the pathophysiology of DUOX2-mediated H2O2 formation in the pancreas further, we demonstrate here that IFN-γ-treated BxPC-3 and CFPAC-1 pancreatic cancer cells (known to increase DUOX2 expression) produce significant levels of intracellular oxidants and extracellular H2O2 which correlate with concomitant up-regulation of VEGF-A and HIF-1α transcription. These changes are not observed in the PANC-1 line that does not increase DUOX2 expression following IFN-γ treatment. DUOX2 knockdown with short interfering RNA significantly decreased IFN-γ-induced VEGF-A or HIF-1α up-regulation, as did treatment of pancreatic cancer cells with the NADPH oxidase inhibitor diphenylene iodonium, the multifunctional reduced thiol N-acetylcysteine, and the polyethylene glycol-modified form of the hydrogen peroxide detoxifying enzyme catalase. Increased DUOX2-related VEGF-A expression appears to result from reactive oxygen-mediated activation of ERK signaling that is responsible for AP-1-related transcriptional effects on the VEGF-A promoter. To clarify the relevance of these observations in vivo, we demonstrate that many human pre-malignant pancreatic intraepithelial neoplasms and frank pancreatic cancers express substantial levels of DUOX protein compared to histologically normal pancreatic tissues, and that expression of both DUOX2 and VEGF-A mRNAs is significantly increased in surgically-resected pancreatic cancers compared to the adjacent normal pancreas.

• Authors: Yongzhong Wu, Jennifer L Meitzler, Smitha Antony, Agnes Juhasz, Jiamo Lu, Guojian Jiang, Han Liu, Melinda Hollingshead, Diana C Haines, Donna Butcher, Michaela S Panter, Krishnendu Roy, James H Doroshow
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 42 Pg. 68412-68433 (10 18 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27637085 (Publication Type: Journal Article)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Onium Compounds
• Vascular Endothelial Growth Factor A
• diphenyleneiodonium
• Interferon-gamma
• Hydrogen Peroxide
• Dual Oxidases
• Extracellular Signal-Regulated MAP Kinases

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Animals
• Cell Line, Tumor
• Dual Oxidases (antagonists & inhibitors, genetics, metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Humans
• Hydrogen Peroxide (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Interferon-gamma (pharmacology)
• Mice, Nude
• Onium Compounds (pharmacology)
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• RNA Interference
• Transplantation, Heterologous
• Vascular Endothelial Growth Factor A (genetics, metabolism)