Abstract
Hypoxia‐inducible factor‐2α (HIF‐2α) plays an important role in increasing cancer progression and distant metastasis in a variety of tumour types. We aimed to investigate its biological function and clinical significance in human pancreatic ductal adenocarcinoma (PDAC). A total of 283 paired PDAC tissues and adjacent normal tissues were collected from patients who underwent surgery or biopsy at Sun Yat‐sen Memorial Hospital between February 2004 and October 2016. In this study, we noted that HIF‐2α expression was significantly up‐regulated in PDAC, positively associated with disease stage, lymph‐node metastasis and patient survival, and identified as an independent prognostic factor of PDAC patients. We demonstrated that HIF‐2α silencing could reduce proliferation, migration and invasion of PDAC cells in vitro. The similar effect on growth was demonstrated in vivo. Furthermore, we noted that knock‐down of HIF‐2α significantly decreased the expression of glutamate oxaloacetate transaminase 1 (GOT1). Importantly, we confirmed that the PI3K/mTORC2 pathway promoted GOT1 expression by targeting HIF‐2α. Our study validated HIF‐2α was an important factor in PDAC progression and poor prognosis and may promote non‐canonical glutamine metabolism via activation of PI3K/mTORC2 pathway. Targeting HIF‐2α represents a novel prognostic biomarker and therapeutic target for patients with PDAC.
Highlights
Pancreatic cancer is a typical hypoxia digestive solid malignancy
Previous research showed that human pancreatic ductal adenocarcinoma (PDAC) utilizes a special metabolism pathway, a non-canonical pathway of glutamine, in which glutamine-derived aspartate is converted into oxaloacetate by aspartate transaminase (GOT1), and this oxaloacetate is converted into malate and pyruvate, increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state [6, 7]
Our findings strongly indicate that Hypoxia-inducible factor-2a (HIF-2a) participates in PDAC carcinogenesis and could regulated non-canonical glutamine metabolism by activation of phosphatidylinositol 3-kinase (PI3K)/ mTORC2 pathway
Summary
Pancreatic cancer is a typical hypoxia digestive solid malignancy. Aberrant metabolism is considered as one of the hallmarks of cancer [3]. Previous research showed that human PDAC utilizes a special metabolism pathway, a non-canonical pathway of glutamine, in which glutamine-derived aspartate is converted into oxaloacetate by aspartate transaminase (GOT1), and this oxaloacetate is converted into malate and pyruvate, increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state [6, 7]. Reprogramming of energy metabolism is the hallmark progression in the research of malignancy neoplasm [3]. It can balance energy metabolism and biosynthesis to maintain the high malignancy behaviours [8]
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