HIF-2α regulates non-canonical glutamine metabolism via activation of PI3K/mTORC2 pathway in human pancreatic ductal adenocarcinoma

Hypoxia-inducible factor-2 alpha (HIF-2 alpha) 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-2 alpha 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-2 alpha 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-2 alpha significantly decreased the expression of glutamate oxaloacetate transaminase 1 (GOT1). Importantly, we confirmed that the PI3K/mTORC2 pathway promoted GOT1 expression by targeting HIF-2 alpha. Our study validated HIF-2 alpha 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-2 alpha represents a novel prognostic biomarker and therapeutic target for patients with PDAC.