Beijing Neurosurgical Institute, Capital Medical University, TianTanXiLi6, Beijing, 100050, China.
Chinese Medical Association, Beijing, 100710, China.
J Endocrinol Invest. 2019 Feb;42(2):137-148. doi: 10.1007/s40618-018-0890-4. Epub 2018 Apr 24.
Protein phosphorylation plays a key role in tumorigenesis and progression. However, little is known about the phosphoproteome profiles of growth hormone-secreting pituitary adenomas (GH-PAs). The aim of this study was to identify critical biomarkers and signaling pathways that might play important roles in GH-PAs and may, therefore, represent potential therapeutic targets.
The differential phosphoprotein expression patterns involved in GH-PAs were investigated by nano-LC-MS/MS in a group of samples. The phosphoprotein expression data were analyzed by bioinformatics. The expression levels of the candidate phosphorylated AMPK (ser496) and ATF2 (ser112) were validated by Western blot analysis in another group of samples.
A total of 1213 phosphorylated protein sites corresponding to 667 proteins were significantly different between GH-PAs and healthy pituitary glands. Among these phosphorylated sites, 871 exhibited lower levels of phosphorylation in GH-PAs. Moreover, 140 novel phosphosites corresponding to 93 proteins were differentially phosphorylated between GH-PAs and healthy pituitary glands, 101 of which showed decreased phosphorylation in GH-PAs. The majority of differentially expressed phosphorylated proteins were significantly enriched in glycolysis and the AMPK signaling pathway in GH-PAs. The AMPK signaling pathway was demonstrated to be inhibited in GH-PAs by pathway activity analysis (z score = - 2.324). Notably, the phosphorylated levels of AMPK (ser496) and ATF2 (ser112) were significantly lower in GH-PAs than in healthy pituitary glands.
These findings suggest that decreased phosphorylation of the AMPK/ATF2 pathway may be critical for glucose metabolism and tumorigenesis in GH-PAs.
蛋白质磷酸化在肿瘤发生和进展中起着关键作用。然而，关于生长激素分泌性垂体腺瘤（GH-PAs）的磷酸蛋白质组谱知之甚少。本研究旨在确定可能在 GH-PAs 中发挥重要作用的关键生物标志物和信号通路，这些标志物和通路可能代表潜在的治疗靶点。
通过纳米 LC-MS/MS 在一组样本中研究 GH-PAs 中涉及的差异磷酸蛋白表达模式。通过生物信息学分析磷酸蛋白表达数据。通过 Western blot 分析在另一组样本中验证候选磷酸化 AMPK（ser496）和 ATF2（ser112）的表达水平。
GH-PAs 与健康垂体之间共有 1213 个磷酸化蛋白位点（对应于 667 种蛋白）存在显著差异。在这些磷酸化位点中，871 个在 GH-PAs 中表现出较低的磷酸化水平。此外，GH-PAs 与健康垂体之间存在 140 个新型磷酸化位点（对应于 93 种蛋白），其中 101 个在 GH-PAs 中显示出较低的磷酸化水平。差异表达的磷酸化蛋白大多数在 GH-PAs 中显著富集于糖酵解和 AMPK 信号通路。通过途径活性分析（z 评分=-2.324）证实，GH-PAs 中的 AMPK 信号通路被抑制。值得注意的是，GH-PAs 中 AMPK（ser496）和 ATF2（ser112）的磷酸化水平明显低于健康垂体。
这些发现表明，AMPK/ATF2 途径的磷酸化降低可能对 GH-PAs 中的葡萄糖代谢和肿瘤发生至关重要。
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