Oncotarget

Research Papers:

ERO1α promotes hypoxic tumor progression and is associated with poor prognosis in pancreatic cancer

Nikhil Gupta, Jung Eun Park, Wilford Tse, Jee Keem Low, Oi Lian Kon, Neil McCarthy and Siu Kwan Sze _

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Oncotarget. 2019; 10:5970-5982. https://doi.org/10.18632/oncotarget.27235

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Abstract

Nikhil Gupta1, Jung Eun Park1, Wilford Tse1, Jee Keem Low2, Oi Lian Kon3, Neil McCarthy4 and Siu Kwan Sze1

1 School of Biological Sciences, Nanyang Technological University, Singapore

2 Department of Surgery, Tan Tock Seng Hospital, Singapore

3 National Cancer Centre Singapore, Division of Medical Sciences, Singapore

4 Centre for Immunobiology, The Blizard Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom

Correspondence to:

Siu Kwan Sze,email: [email protected]

Keywords: pancreatic cancer; hypoxia tumor; ERO1α; SILAC; proteomics

Received: July 15, 2019     Accepted: September 24, 2019     Published: October 15, 2019

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.


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