Abstract
Hypoxia and the hypovascular tumor microenvironment are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is of great importance to tumor survival and proliferation. There is little research regarding the role of Nuclear Factor of Activated T Cells 5 (NFAT5) in relation to carcinoma. Here, we explored the impact of NFAT5 on the biological behavior of PDAC and the underlying mechanism. We demonstrated that NFAT5 was highly expressed in PDAC and was related to poorer prognosis. Knockdown of NFAT5 lead to impaired proliferation of tumor cells caused by an aberrant Warburg effect. Mechanically, phosphoglycerate kinase 1 (PGK-1), which is the first enzyme generating ATP in glycolysis, was verified as a target gene of NFAT5. Over-expression of PGK1 compromised the aberrant oncological behavior caused by knockdown of NFAT5 both in vitro and in vivo. Clinical samples underwent positron emission tomography-computed tomography (PET-CT) examination and KrasG12D/+/Trp53R172H/+/Pdx1-Cre (KPC) mice were collected to support our conclusion.
Highlights
Pancreatic cancer is one of the most aggressive and lethal malignant tumors, with a continuously rising mortality[1,2]
(see figure on previous page) Fig. 4 Nuclear Factor of Activated T Cells 5 (NFAT5) promoted pancreatic ductal adenocarcinoma (PDAC) cell growth by enhancing the Warburg effect. a Gene set enrichment analysis (GSEA) of the NFAT5 highexpression group and the low-expression group using hallmark gene sets showed the relationship between NFAT5 and three datasets closely related to the Warburg effect
NES, normalized enrichment score. b The correlation between NFAT5 and glycolytic enzymes. c Relative mRNA levels of glycolysis-related genes of PDAC with or without NFAT5 knockdown. d, e Glycolytic function and mitochondrial stress test of NFAT5 knockdown AsPC-1 and BxPC-3 cells treated with shRNA were measured by extracellular acidification rate (d) and oxygen consumption rate (e), respectively. f Relative glucose consumption and lactate production in normal and NFAT5 knockdown AsPC-1 and BxPC-3 cell lines. g NFAT5 knockdown AsPC-1 and BxPC-3 cell proliferation capability indicated no difference after glucose was replaced with galactose compared to normal AsPC-1 and BxPC-3 cells. h Typical immunohistochemical images of NFAT5 low and high-expression group along with their CT and positron emission tomography-computed tomography (PET-CT) images
Summary
Pancreatic cancer is one of the most aggressive and lethal malignant tumors, with a continuously rising mortality[1,2]. Pancreatic cancer ranks fourth among the fatal malignant tumors in western countries and sixth in China; its 5-year survival rate is only 7% or lower[2,3,4]. There is increasing evidence of the pro-tumor role of the NFAT (Nuclear Factor of Activated T cell) family in multiple kinds of malignancies. The specific role of these transcription factors in pancreatic ductal adenocarcinoma (PDAC) has not been well-studied. We found that all five transcription factors are highly expressed in tumor tissue, and the expression of NFAT5 is negatively associated with prognosis. NFAT5 (Nuclear Factor Of Activated T Cells 5) was first recognized as a tonicity-regulated transcription factor (Ton/EBP) that
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