Proteotranscriptomic Analysis Reveals Stage Specific Changes in the Molecular Landscape of Clear-Cell Renal Cell Carcinoma.
Proteotranscriptomic Analysis Reveals Stage Specific Changes in the Molecular Landscape of Clear-Cell Renal Cell Carcinoma.
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DOI：
10.1371/journal.pone.0154074
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Drake RR
中科院分区：
文献类型：
--
作者：
Neely BA;Wilkins CE;Marlow LA;Malyarenko D;Kim Y;Ignatchenko A;Sasinowska H;Sasinowski M;Nyalwidhe JO;Kislinger T;Copland JA;Drake RR
肾细胞癌占成人恶性肿瘤的2%至3%，其中最常见的亚型是透明细胞RCC（ccRCC）。这种类型的癌症在基因组和转录组水平上得到了很好的表征，并且与导致HIF 1稳定的VHL缺失相关。目前的研究重点是在蛋白质组水平上评估ccRCC阶段依赖性变化，以深入了解ccRCC进展的分子发病机制。为了实现这一目标，使用无标记蛋白质组学来表征来自84名I至IV期ccRCC患者的匹配肿瘤和正常相邻组织。使用合并的样品鉴定了1551种蛋白质，其中290种是差异丰富的，而使用单个样品鉴定了783种蛋白质，其中344种是差异丰富的。这344种差异丰富的蛋白质在代谢途径中富集，进一步检查显示代谢功能障碍与瓦尔堡效应一致。此外，蛋白质数据表明ESRRA和ESRRG和HIF 1A的激活，以及FOXA 1，MAPK 1和WISP 2的抑制。对47对这些相同组织的互补基因表达阵列数据的子集分析表明类似的上游变化，例如随着阶段增加HIF 1A激活，尽管从转录组数据中无法预测ESRRA和ESRRG激活和FOXA 1抑制。ESRRA和ESRRG的激活意味着HIF 2A也可能在ccRCC的后期阶段被激活，这在转录分析中得到了证实。这种联合分析强调了HIF 1A和HIF 2A在形成ccRCC分子表型中的重要性，以及ESRRA和ESRRG在驱动这些变化中的潜在参与。此外，cofilin-1、profilin-1、烟酰胺N-甲基转移酶和果糖-二磷酸醛缩酶A被鉴定为晚期ccRCC的候选标志物。利用从异质生物领域收集的数据加强了每个领域的研究结果，表明这种分析的互补性。总之，这些结果突出了VHL/HIF 1A/HIF 2A轴的重要性，并为未来的研究提供了基础和治疗靶点。(Data可通过ProteomeXchange（标识符PXD 003271）和MassIVE（标识符MSV 000079511）获得。
Renal cell carcinoma comprises 2 to 3% of malignancies in adults with the most prevalent subtype being clear-cell RCC (ccRCC). This type of cancer is well characterized at the genomic and transcriptomic level and is associated with a loss of VHL that results in stabilization of HIF1. The current study focused on evaluating ccRCC stage dependent changes at the proteome level to provide insight into the molecular pathogenesis of ccRCC progression. To accomplish this, label-free proteomics was used to characterize matched tumor and normal-adjacent tissues from 84 patients with stage I to IV ccRCC. Using pooled samples 1551 proteins were identified, of which 290 were differentially abundant, while 783 proteins were identified using individual samples, with 344 being differentially abundant. These 344 differentially abundant proteins were enriched in metabolic pathways and further examination revealed metabolic dysfunction consistent with the Warburg effect. Additionally, the protein data indicated activation of ESRRA and ESRRG, and HIF1A, as well as inhibition of FOXA1, MAPK1 and WISP2. A subset analysis of complementary gene expression array data on 47 pairs of these same tissues indicated similar upstream changes, such as increased HIF1A activation with stage, though ESRRA and ESRRG activation and FOXA1 inhibition were not predicted from the transcriptomic data. The activation of ESRRA and ESRRG implied that HIF2A may also be activated during later stages of ccRCC, which was confirmed in the transcriptional analysis. This combined analysis highlights the importance of HIF1A and HIF2A in developing the ccRCC molecular phenotype as well as the potential involvement of ESRRA and ESRRG in driving these changes. In addition, cofilin-1, profilin-1, nicotinamide N-methyltransferase, and fructose-bisphosphate aldolase A were identified as candidate markers of late stage ccRCC. Utilization of data collected from heterogeneous biological domains strengthened the findings from each domain, demonstrating the complementary nature of such an analysis. Together these results highlight the importance of the VHL/HIF1A/HIF2A axis and provide a foundation and therapeutic targets for future studies. (Data are available via ProteomeXchange with identifier PXD003271 and MassIVE with identifier MSV000079511.)