STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect.
STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect.
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DOI：
10.1186/1741-7015-7-68
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发表时间：
2009-11-05
期刊：
影响因子：
9.3
通讯作者：
Khodarev NN
中科院分区：
文献类型：
--
作者：
Pitroda SP;Wakim BT;Sood RF;Beveridge MG;Beckett MA;MacDermed DM;Weichselbaum RR;Khodarev NN
信号转导和转录激活因子1（STAT 1）传统上被认为是干扰素信号传导的递质和促凋亡肿瘤抑制因子。最近的数据已经确定了与肿瘤发生和抵抗遗传毒性应激（包括电离辐射（IR）和化疗）相关的STAT 1的新功能。为了研究STAT 1致瘤功能的机制，我们进行了联合转录组学-蛋白质组学表达分析，发现STAT 1与能量代谢的调节有关，可能与瓦尔堡效应有关。我们在SCC 61人鳞状细胞癌细胞系中产生了稳定的STAT 1敲除，在无胸腺小鼠中建立了肿瘤异种移植物，并比较了STAT 1野生型（WT）和敲除（KD）未处理或辐照（IR）肿瘤的转录组学和蛋白质组学特征。转录谱分析基于Affyscore Human GeneChip® Gene 1.0 ST微阵列。通过对UniProt数据库的人类子集进行搜索，从串联质谱（MS/MS）数据中确定蛋白质组。使用用于核糖核酸的微阵列的显著性分析和用于蛋白质的可视化软件分析数据。功能分析用免疫途径分析进行，统计学显著性用Fisher精确检验测量。STAT 1的敲除导致未治疗肿瘤的显著生长抑制和照射肿瘤的放射增敏。这些变化伴随着糖酵解/糖异生（GG），柠檬酸循环（CC）和氧化磷酸化（OP）的基因和蛋白质表达的改变。在这些途径中，GG在基因和蛋白质表达方面具有最一致的变化，并且证明了与肿瘤特异性糖酵解一致的基因和蛋白质的STAT 1依赖性表达。此外，IR显著抑制了STAT 1 KD肿瘤中的GG通路，而STAT 1 WT肿瘤中没有显著变化。我们的研究结果确定了一个以前未表征的功能的STAT 1在肿瘤中：表达调控基因编码的蛋白质参与糖酵解，柠檬酸循环和线粒体氧化磷酸化，糖酵解基因的主要调控。糖酵解的STAT 1依赖性表达调节表明STAT 1作为负责瓦尔堡效应的基因的转录调节剂的潜在作用。
The Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor. Recent data have identified new functions of STAT1 associated with tumourigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumourigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis and found that STAT1 is associated with regulation of energy metabolism with potential implication in the Warburg effect. We generated a stable knockdown of STAT1 in the SCC61 human squamous cell carcinoma cell line, established tumour xenografts in athymic mice, and compared transcriptomic and proteomic profiles of STAT1 wild-type (WT) and knockdown (KD) untreated or irradiated (IR) tumours. Transcriptional profiling was based on Affymetrix Human GeneChip® Gene 1.0 ST microarrays. Proteomes were determined from the tandem mass spectrometry (MS/MS) data by searching against the human subset of the UniProt database. Data were analysed using Significance Analysis of Microarrays for ribonucleic acid and Visualize software for proteins. Functional analysis was performed with Ingenuity Pathway Analysis with statistical significance measured by Fisher's exact test. Knockdown of STAT1 led to significant growth suppression in untreated tumours and radio sensitization of irradiated tumours. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis/gluconeogenesis (GG), the citrate cycle (CC) and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumour-specific glycolysis. In addition, IR drastically suppressed the GG pathway in STAT1 KD tumours without significant change in STAT1 WT tumours. Our results identify a previously uncharacterized function of STAT1 in tumours: expressional regulation of genes encoding proteins involved in glycolysis, the citrate cycle and mitochondrial oxidative phosphorylation, with predominant regulation of glycolytic genes. STAT1-dependent expressional regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect.
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