Transcription factor NFAT5 contributes to the glycolytic phenotype rewiring and pancreatic cancer progression via transcription of PGK1
Transcription factor NFAT5 contributes to the glycolytic phenotype rewiring and pancreatic cancer progression via transcription of PGK1
复制标题
转录因子 NFAT5 通过 PGK1 转录促进糖酵解表型重新布线和胰腺癌进展
DOI：
10.1038/s41419-019-2072-5
复制
发表时间：
2019-12-11
影响因子：
9
通讯作者：
Sun, Yongwei
中科院分区：
文献类型：
--
作者：
Jiang, Yongsheng;He, Ruizhe;Sun, Yongwei
低氧和低血管的肿瘤微环境是胰腺导管腺癌(PDAC)的主要特征，糖酵解对肿瘤的生存和增殖具有重要意义。关于活化T细胞核因子5(NFAT5)在癌症中的作用的研究很少。在此，我们探讨了NFAT5对PDAC生物学行为的影响及其机制。我们发现NFAT5在PDAC中高表达，且与预后不良有关。由于异常的Warburg效应，NFAT5基因的敲除导致肿瘤细胞的增殖受损。磷酸甘油酸激酶1(PGK-1)是糖酵解过程中第一个产生三磷酸腺苷的酶，从机制上被证实是NFAT5的靶基因。在体外和体内，过表达的PGK1均可抑制NFAT5基因敲除所引起的肿瘤异常行为。临床标本进行正电子发射断层扫描-计算机断层扫描(PET-CT)检查，并收集KrasG12D/+/Trp53R172H/+/Pdx1-Cre(KPC)小鼠来支持我们的结论。
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.