CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, China.
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, China.
Int J Cancer. 2018 Jul 15;143(2):396-407. doi: 10.1002/ijc.31313. Epub 2018 Mar 6.
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.
遗传改变驱动代谢重编程，以满足癌症细胞在不利环境中增殖和存活对生物合成前体和能量的增加需求。对基因-代谢物调控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相邻正常组织（ANTs）进行了基于气相色谱-质谱（GC-MS）的代谢组学和 RNA 测序分析，以阐明 PCa 中的分子改变和潜在的潜在调控机制。在肿瘤组织中观察到代谢中间产物的显著积累和三羧酸（TCA）循环中基因的富集，表明 TCA 循环在 PCa 组织中过度激活。此外，延胡索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，并且与参与支链氨基酸降解的基因表达显著相关。使用综合组学方法，我们进一步揭示了从丙酮酸、谷氨酰胺分解和支链氨基酸（BCAA）降解中潜在的补料途径，为 TCA 循环补充代谢物。综合组学技术能够进行基于网络的分析，从而全面深入地了解 PCa 的病理生理学，并可能有助于开发新的有效治疗策略。
