Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer
Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer
复制标题
代谢组学和转录组学概况揭示了前列腺癌中三羧酸循环的失调及相关机制
DOI：
10.1002/ijc.31313
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发表时间：
2018-07-15
影响因子：
6.4
通讯作者：
Xu, Guowang
中科院分区：
文献类型：
--
作者：
Shao, Yaping;Ye, Guozhu;Xu, Guowang
基因改变驱动代谢重编程，以满足癌细胞在不利环境中增殖和生存所需的生物合成前体和能量需求。对基因代谢调节网络和代谢失调的系统研究应该揭示前列腺癌（PCa）发病机制的分子机制。在此，我们对前列腺肿瘤和匹配的邻近正常组织（ANT）进行了基于气相色谱-质谱（GC-MS）的代谢组学和RNA-seq分析，以阐明PCa中的分子改变和潜在的潜在调节机制。在肿瘤组织中观察到代谢中间体的显着积累和三羧酸（TCA）循环中的基因富集，表明 PCa 组织中 TCA 循环过度激活。此外，富马酸和苹果酸的水平与Gleason评分、肿瘤分期和编码相关酶的基因表达高度相关，并且与支链氨基酸降解相关基因的表达显着相关。使用综合组学方法，我们进一步揭示了丙酮酸、谷氨酰胺分解代谢和支链氨基酸（BCAA）降解的潜在回补途径，有助于补充 TCA 循环的代谢物。集成组学技术能够进行基于网络的分析，以全面、深入地了解 PCa 病理生理学，并可能促进新的有效治疗策略的开发。有什么新鲜事？尽管许多研究报告了前列腺癌 (PCa) 细胞中三羧酸 (TCA) 循环的加速，但潜在的代谢重编程和分子机制仍然难以捉摸。在这里，作者通过匹配的正常组织和 PCa 组织的代谢组学和转录组学分析，系统地研究了 TCA 循环的分子变化。研究发现富马酸和苹果酸与肿瘤进展和相关基因的表达高度相关。来自丙酮酸、谷氨酰胺分解代谢和支链氨基酸降解的潜在回补途径有助于补充 TCA 循环的代谢物。这些观察结果为 PCa 致癌提供了新的分子见解，并可能促进新的有效治疗策略的开发。
Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography-mass spectrometry (GC-MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network-based analyses to gain a comprehensive and in-depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies.What's new?Although many studies have reported accelerated tricarboxylic acid (TCA) cycle in prostate cancer (PCa) cells, the underlying metabolic reprogramming and molecular mechanisms remain elusive. Here, the authors systematically investigated the molecular changes in TCA cycle through metabolomics and transcriptomics analysis of matched normal and PCa tissues. Fumarate and malate were found to be highly correlated with tumor progression and expression of related genes. Potential anaplerotic routes from pyruvate, glutamine catabolism, and BCAA degradation contributed to replenishing metabolites for TCA cycle. These observations provide new molecular insight into PCa carcinogenesis and may facilitate the development of new and effective therapeutic strategies.