Alkatout Ibrahim, Friemel Juliane, Sitek Barbara, Anlauf Martin, Eisenach Patricia A, Stühler Kai, Scarpa Aldo, Perren Aurel, Meyer Helmut E, Knoefel Wolfram T, Klöppel Günter, Sipos Bence
Clinic of Gynecology and Obstetrics, University Hospitals Schleswig-Holstein, Kiel, Germany.
Institute of Pathology, University of Zurich, Zurich, Switzerland.
Mod Pathol. 2015 Jan;28(1):69-79. doi: 10.1038/modpathol.2014.82. Epub 2014 Jun 20.
The prognosis of pancreatic neuroendocrine tumors is related to size, histology and proliferation rate. However, this stratification needs to be refined further. We conducted a proteome study on insulinomas, a well-defined pancreatic neuroendocrine tumor entity, in order to identify proteins that can be used as biomarkers for malignancy. Based on a long follow-up, insulinomas were divided into those with metastases (malignant) and those without (benign). Microdissected cells from six benign and six malignant insulinomas were subjected to a procedure combining fluorescence dye saturation labeling with high-resolution two-dimensional gel electrophoresis. Differentially expressed proteins were identified using nano liquid chromatography-electrospray ionization/multi-stage mass spectrometry and validated by immunohistochemistry on tissue microarrays containing 62 insulinomas. Sixteen differentially regulated proteins were identified among 3000 protein spots. Immunohistochemical validation revealed that aldehyde dehydrogenase 1A1 and voltage-dependent anion-selective channel protein 1 showed significantly stronger expression in malignant insulinomas than in benign insulinomas, whereas tumor protein D52 (TPD52) binding protein was expressed less strongly in malignant insulinomas than in benign insulinomas. Using multivariate analysis, low TPD52 expression was identified as a strong independent prognostic factor for both recurrence-free and overall disease-related survival.
胰腺神经内分泌肿瘤的预后与肿瘤大小、组织学类型及增殖率有关。然而，这种分层还需要进一步细化。我们对胰岛素瘤（一种明确的胰腺神经内分泌肿瘤实体）进行了蛋白质组学研究，以鉴定可作为恶性肿瘤生物标志物的蛋白质。基于长期随访，胰岛素瘤被分为有转移的（恶性）和无转移的（良性）。从6个良性和6个恶性胰岛素瘤中显微切割得到的细胞，采用荧光染料饱和标记与高分辨率二维凝胶电泳相结合的方法进行处理。使用纳升液相色谱 - 电喷雾电离/多级质谱法鉴定差异表达的蛋白质，并通过对包含62个胰岛素瘤的组织微阵列进行免疫组织化学验证。在3000个蛋白点中鉴定出16种差异调节的蛋白质。免疫组织化学验证显示，醛脱氢酶1A1和电压依赖性阴离子选择性通道蛋白1在恶性胰岛素瘤中的表达明显强于良性胰岛素瘤，而肿瘤蛋白D52（TPD52）结合蛋白在恶性胰岛素瘤中的表达强度低于良性胰岛素瘤。通过多变量分析，低TPD52表达被确定为无复发生存和总体疾病相关生存的强有力独立预后因素。
