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Title: ERO1α promotes hypoxic tumor progression and is associated with poor prognosis in pancreatic cancer
Authors: Gupta, Nikhil
Park, Jung Eun
Tse, Wilford
Low, Jee Keem
Kon, Oi Lian
McCarthy, Neil
Sze, Siu Kwan
Keywords: Science::Biological sciences
Issue Date: 2019
Source: Gupta, N., Park, J. E., Tse, W., Low, J. K., Kon, O. L., McCarthy, N., & Sze, S. K. (2019). ERO1α promotes hypoxic tumor progression and is associated with poor prognosis in pancreatic cancer. Oncotarget, 10(57), 5970-5982. doi:10.18632/oncotarget.27235
Journal: Oncotarget
Abstract: Pancreatic cancer is a leading cause of mortality worldwide due to the difficulty of detecting early-stage disease and our poor understanding of the mediators that drive progression of hypoxic solid tumors. We therefore used a heavy isotope 'pulse/trace' proteomic approach to determine how hypoxia (Hx) alters pancreatic tumor expression of proteins that confer treatment resistance, promote metastasis, and suppress host immunity. Using this method, we identified that hypoxia stress stimulates pancreatic cancer cells to rapidly translate proteins that enhance metastasis (NOTCH2, NCS1, CD151, NUSAP1), treatment resistance (ABCB6), immune suppression (NFIL3, WDR4), angiogenesis (ANGPT4, ERO1α, FOS), alter cell metabolic activity (HK2, ENO2), and mediate growth-promoting cytokine responses (CLK3, ANGPTL4). Database mining confirmed that elevated gene expression of these hypoxia-induced mediators is significantly associated with poor patient survival in various stages of pancreatic cancer. Among these proteins, the oxidoreductase enzyme ERO1α was highly sensitive to induction by hypoxia stress across a range of different pancreatic cancer cell lines and was associated with particularly poor prognosis in human patients. Consistent with these data, genetic deletion of ERO1α substantially reduced growth rates and colony formation by pancreatic cancer cells when assessed in a series of functional assays in vitro. Accordingly, when transferred into a mouse xenograft model, ERO1α-deficient tumor cells exhibited severe growth restriction and negligible disease progression in vivo. Together, these data indicate that ERO1α is potential prognostic biomarker and novel drug target for pancreatic cancer therapy.
ISSN: 1949-2553
DOI: 10.18632/oncotarget.27235
Rights: © 2019 Gupta et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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