Associations of PGK1 promoter hypomethylation and PGK1-mediated PDHK1 phosphorylation with cancer stage and prognosis: a TCGA pan-cancer analysis
Associations of PGK1 promoter hypomethylation and PGK1-mediated PDHK1 phosphorylation with cancer stage and prognosis: a TCGA pan-cancer analysis
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DOI：
10.1186/s40880-019-0401-9
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发表时间：
2019-10-02
影响因子：
16.2
通讯作者：
He, Jie
中科院分区：
文献类型：
--
作者：
Shao, Fei;Yang, Xueying;He, Jie
背景：癌细胞为了增殖而重新编程代谢。磷酸甘油酸激酶1（PGK1）是一种糖酵解酶，是新近发现的一种蛋白激酶，它协调糖酵解和线粒体代谢。然而，PGK1表达和功能在癌症进展中的临床意义尚不清楚。在这里，我们研究了多种癌症类型的进展和预后与PGK1表达及其在线粒体代谢调节中的功能之间的关系。方法：我们在The Cancer Genome Atlas数据集中对34种癌症类型的11，908例肿瘤组织和1582例配对正常组织进行了PGK1 mRNA水平和DNA甲基化的泛癌分析。使用特异性抗体对PGK1 S203和PDHK1 T338磷酸化，我们进行了免疫组织化学与组织芯片分析，在另外818例癌症病例和619对正常组织从5个癌症type.Results：PGK1 mRNA水平显着升高与低甲基化的启动子区域，并与先进的TNM分期分别在15和4个癌症类型。在乳腺癌中，PGK1 mRNA水平升高和启动子低甲基化与预后不良相关。PGK1 S203和PDHK1 T338磷酸化水平正相关与乳腺癌、肝癌、肺癌、胃癌和食管癌的短总生存期（OS）以及乳腺癌和食管癌的晚期TNM分期显著相关。PGK 1 p5203和PDHK 1 pT338也是肝癌、肺癌和胃癌短OS的独立预测因素。结论：PGK 1和PDHK 1的表达升高、启动子低甲基化和磷酸化与不同类型癌症的疾病进展和短OS相关。PGK1和PDHK1磷酸化可能是潜在的预后生物标志物。
Background: Cancer cells reprogram metabolism for proliferation. Phosphoglycerate kinase 1 (PGK1), as a glycolytic enzyme and newly identified protein kinase, coordinates glycolysis and mitochondrial metabolism. However, the clinical significance of PGK1 expression and function in cancer progression is unclear. Here, we investigated the relationship between the progression and prognosis of multiple cancer types and PGK1 expression and its function in the mitochondrial metabolism regulation.Methods: We performed pan-cancer analyses of PGK1 mRNA level and DNA methylation in 11,908 tumor tissues and 1582 paired normal tissues across 34 cancer types in The Cancer Genome Atlas datasets. Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation, we performed immunohistochemistry with tissue microarray assay in additional 818 cancer cases with 619 paired normal tissues from five cancer types.Results: The PGK1 mRNA level was significantly elevated with hypomethylation in promotor regions and associated with advanced TNM stage in 15 and four cancer types, respectively. In breast carcinoma, elevated PGK1 mRNA level and promoter hypomethylation were associated with poor prognosis. Positively correlated PGK1 S203 and PDHK1 T338 phosphorylation levels were significantly associated with short overall survival (OS) in cancers of the breast, liver, lung, stomach, and esophagus and with advanced TNM stage in breast and esophageal cancers. PGK1 p5203 and PDHK1 pT338 were also independent predictors of short OS in liver, lung, and stomach cancer.Conclusions: The elevated expression, promoter hypomethylation, and phosphorylation of PGK1 and PDHK1 were related with disease progression and short OS in diverse types of cancer. PGK1 and PDHK1 phosphorylation may be potential prognostic biomarkers.