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

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.

Prognostic Role of Hypoxia-Inducible Factor-2α Tumor Cell Expression in Cancer Patients: A Meta-Analysis

“…A total of 38 from the selected 49 studies investigated the association between HIF-2α and OS. All the necessary information to estimate the HR could not be obtained from two papers and were therefore not included in the analysis (Table S1 in Supplementary Material) ( 21 , 23 , 24 , 26 – 31 , 33 – 35 , 37 – 39 , 41 – 43 , 45 , 46 , 48 , 49 , 51 , 52 , 54 – 57 , 59 , 60 , 62 – 69 ). Based on these studies, high HIF-2α expression was statistically significantly associated with a decreased OS (HR = 1.69, 95% CI 1.39–2.06, p < 0.0001, Figure 3 ).…”

“… Forest plot of hazard ratios (HRs) with 95% confidence interval (95% CI) (horizontal bars) for the association of hypoxia-inducible factor-2α expression and overall survival (OS). Symbol size represents the assigned weight of the study ( 21 , 24 , 26 , 28 , 30 , 31 , 33 – 35 , 37 , 38 , 41 – 43 , 45 , 46 , 48 , 49 , 52 , 54 – 57 , 59 , 60 , 62 – 64 , 66 – 69 ). …”

“…Progression-free survival was reported in 5 of 49 included studies, of which 1 study provided incomplete data (Table S1 in Supplementary Material) and 2 described patients with renal cell cancer ( 29 , 39 , 48 , 51 , 53 ). Similar to the other endpoints, PFS was significantly shorter (HR = 2.18, 95% CI 1.25–3.78, p = 0.0058) in patients with tumors expressing high levels of HIF-2α (Figure 8 ).…”

Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms

“…GPC5 was involved in transcription factor complex, TFRC1, oncogenic signatures (HOXA9 and BMI1), gene methylation, phospholipid metabolic process, glycerophospholipid metabolism, cell cycle, and EGFR pathway. For pancreatic cancer, the transcription factor, hif-2α, can speed up metabolism and promote tumor proliferation and high level of hif-2α correlates with worse patients OS (61,62). Methylation status of GRAP2, ICAM3, A2ML1, MUC1 and MUC4 can in uence expression of these genes, which is associated with survival of pancreatic cancer (63,64).…”

Differential Impact of Flavonoids on Redox Modulation, Bioenergetics, and Cell Signaling in Normal and Tumor Cells: A Comprehensive Review

“…In addition, glycolytic metabolites such as lactate and pyruvate also stabilize HIF-1α via a hypoxia-independent mechanism and establish a positive loop of HIF-1α activities, suggesting that obesity or insulin resistance could increase the development of cancers ( 57 ). Hypoxia in tumors also leads to overexpression of HIF-2α, which, subsequently, favors cancer cell survival, proliferation, and metastasis involving noncanonical glutamine metabolism as recently shown in human pancreatic ductal adenocarcinoma (PDAC) ( 76 , 136 ).…”