Prostate Cancer Research Center, Faculty of Medicine and Life Sciences and BioMediTech Institute, University of Tampere, Tampere, 33014, Finland.
FimLab Laboratories, Tampere University Hospital, Tampere, 33101, Finland.
Nat Commun. 2018 Mar 21;9(1):1176. doi: 10.1038/s41467-018-03573-6.
To understand functional consequences of genetic and transcriptional aberrations in prostate cancer, the proteomic changes during disease formation and progression need to be revealed. Here we report high-throughput mass spectrometry on clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration resistant prostate cancer (CRPC). Each sample group shows a distinct protein profile. By integrative analysis we show that, especially in CRPC, gene copy number, DNA methylation, and RNA expression levels do not reliably predict proteomic changes. Instead, we uncover previously unrecognized molecular and pathway events, for example, several miRNA target correlations present at protein but not at mRNA level. Notably, we identify two metabolic shifts in the citric acid cycle (TCA cycle) during prostate cancer development and progression. Our proteogenomic analysis uncovers robustness against genomic and transcriptomic aberrations during prostate cancer progression, and significantly extends understanding of prostate cancer disease mechanisms.
为了了解前列腺癌中遗传和转录异常的功能后果，需要揭示疾病形成和进展过程中的蛋白质组变化。在这里，我们报告了对良性前列腺增生（BPH）、未经治疗的原发性前列腺癌（PC）和去势抵抗性前列腺癌（CRPC）的临床组织样本进行高通量质谱分析。每个样本组都显示出独特的蛋白质谱。通过综合分析，我们表明，特别是在 CRPC 中，基因拷贝数、DNA 甲基化和 RNA 表达水平不能可靠地预测蛋白质组变化。相反，我们发现了以前未被认识的分子和途径事件，例如，在蛋白质水平而不是在 mRNA 水平存在几种 miRNA 靶标相关性。值得注意的是，我们在前列腺癌发生和进展过程中发现柠檬酸循环（TCA 循环）中的两个代谢转变。我们的蛋白质基因组分析揭示了前列腺癌进展过程中对基因组和转录组异常的稳健性，并显著扩展了对前列腺癌疾病机制的理解。
