Sheridan Christine Moore, Grogan Tristan R, Nguyen Hao G, Galet Colette, Rettig Matthew B, Hsieh Andrew C, Ruggero Davide
Department of Urology, University of California, San Francisco, CA, USA.
Statistic Core, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Oncotarget. 2015 Apr 10;6(10):7470-80. doi: 10.18632/oncotarget.3477.
Attempts to identify biomarkers to detect prostate tumorigenesis, and thus minimize prostate cancer progression and inform treatment decisions have primarily focused on alterations at the DNA and mRNA levels, ignoring alterations at the level of protein synthesis control. We have previously shown that the PI3K-AKT-mTOR pathway, frequently deregulated in prostate cancer, specifically induces the synthesis of proteins that contribute to metastasis, most notably YB-1 and MTA1, without altering mRNA levels thereby demonstrating the importance of translation control in driving the expression of these genes in cancer.Here, we analyze genomic sequencing and mRNA expression databases, as well as protein expression employing an annotated tissue microarray generated from 332 prostate cancer patients with 15 years of clinical follow-up to determine the combined prognostic capability of YB-1 and MTA1 alterations in forecasting prostate cancer outcomes. Remarkably, protein abundance, but not genomic or transcriptional alterations of YB-1 and MTA1, is predictive of disease recurrence, exhibiting a dose-dependent effect on time to PSA recurrence, an indicator of tumor relapse. Moreover, high protein levels of YB-1 and MTA1 are associated with a 3-fold increased risk for requiring future hormone therapy or radiation therapy. Importantly, YB-1 and MTA1 protein levels significantly increase the predictive capacity of a clinical model for prostate cancer recurrence. These findings demonstrate that protein abundance of YB-1 and MTA1, irrespective of DNA or mRNA status, can predict for prostate cancer relapse and uncover a vast underappreciated repository of biomarkers regulated at the level of protein expression.
试图识别生物标志物以检测前列腺肿瘤发生，从而尽量减少前列腺癌进展并为治疗决策提供依据，主要集中在DNA和mRNA水平的改变上，而忽略了蛋白质合成控制水平的改变。我们之前已经表明，在前列腺癌中经常失调的PI3K-AKT-mTOR通路，特别诱导有助于转移的蛋白质的合成，最显著的是YB-1和MTA1，而不改变mRNA水平，从而证明了翻译控制在驱动这些基因在癌症中表达的重要性。在这里，我们分析了基因组测序和mRNA表达数据库，以及使用从332名前列腺癌患者生成的带有注释的组织微阵列进行蛋白质表达分析，这些患者有15年的临床随访数据，以确定YB-1和MTA1改变在预测前列腺癌预后方面的综合预后能力。值得注意的是，YB-1和MTA1的蛋白质丰度而非基因组或转录改变可预测疾病复发，对PSA复发时间呈现剂量依赖性影响，PSA复发是肿瘤复发的一个指标。此外，YB-1和MTA1的高蛋白水平与未来需要激素治疗或放射治疗的风险增加3倍相关。重要的是，YB-1和MTA1蛋白水平显著提高了前列腺癌复发临床模型的预测能力。这些发现表明，无论DNA或mRNA状态如何，YB-1和MTA1的蛋白质丰度都可以预测前列腺癌复发，并揭示了一个在蛋白质表达水平上大量未被充分认识的生物标志物库。
