Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.
PLoS One. 2013 Aug 5;8(8):e71654. doi: 10.1371/journal.pone.0071654. Print 2013.
The loss of von Hippel-Lindau (VHL) protein function leads to highly vascular renal tumors characterized by an aggressive course of disease and refractoriness to chemotherapy and radiotherapy. Loss of VHL in renal tumors also differs from tumors of other organs in that the oncogenic cascade is mediated by an increase in the levels of hypoxia-inducible factor-2α (HIF2α) instead of hypoxia-inducible factor-1α (HIF1α).
We used renal carcinoma cell lines that recapitulate the differences between mutant VHL and wild-type VHL genotypes. Utilizing a method relying on extracted peptide intensities as a label-free approach for quantitation by liquid chromatography-mass spectrometry, our proteomics study revealed regulation of key proteins important for cancer cell survival, proliferation and stress-resistance, and implicated differential regulation of signaling networks in VHL-mutant renal cell carcinoma. We also observed upregulation of cellular energy pathway enzymes and the stress-responsive mitochondrial 60-kDa heat shock protein. Finding reliance on glutaminolysis in VHL-mutant renal cell carcinoma was of particular significance, given the generally predominant dependence of tumors on glycolysis. The data have been deposited to the ProteomeXchange with identifier PXD000335.
Pathway analyses provided corroborative evidence for differential regulation of molecular and cellular functions influencing cancer energetics, metabolism and cell proliferation in renal cell carcinoma with distinct VHL genotype. Collectively, the differentially regulated proteome characterized by this study can potentially guide translational research specifically aimed at effective clinical interventions for advanced VHL-mutant, HIF2α-over-expressing tumors.
von Hippel-Lindau(VHL)蛋白功能丧失导致高度血管化的肾肿瘤，其疾病进程具有侵袭性且对化疗和放疗具有抗性。肾肿瘤中 VHL 的缺失也不同于其他器官的肿瘤，因为致癌级联反应是由缺氧诱导因子-2α(HIF2α)水平的增加而不是缺氧诱导因子-1α(HIF1α)介导的。
我们使用了 recapitulate 突变 VHL 和野生型 VHL 基因型之间差异的肾癌细胞系。利用一种依赖于提取肽强度的方法作为无标记定量方法通过液相色谱-质谱法，我们的蛋白质组学研究揭示了对癌细胞存活、增殖和应激抗性至关重要的关键蛋白的调节，并暗示了 VHL 突变型肾细胞癌中信号转导网络的差异调节。我们还观察到细胞能量途径酶和应激响应的线粒体 60kDa 热休克蛋白的上调。在 VHL 突变型肾细胞癌中观察到对谷氨酰胺分解的依赖具有特别重要的意义，因为肿瘤通常主要依赖糖酵解。该数据已被 ProteomeXchange 以标识符 PXD000335 进行了存储。
途径分析为影响肾癌细胞癌能学、代谢和细胞增殖的分子和细胞功能的差异调节提供了佐证证据，这些功能具有不同的 VHL 基因型。总的来说，本研究中所描述的差异调节的蛋白质组可能有助于指导专门针对 VHL 突变、HIF2α过表达肿瘤的有效临床干预的转化研究。
