Tretiakova Maria, Zynger Debra L, Luan Chunyan, Andeen Nicole K, Finn Laura S, Kocherginsky Masha, Teh Bin T, Yang Ximing J
Department of Pathology, University of Washington, 325 9th Ave, Seattle, WA, 98104, USA,
Virchows Arch. 2015 Jan;466(1):67-76. doi: 10.1007/s00428-014-1669-4. Epub 2014 Nov 4.
Glypican 3 (GPC3), a heparan sulfate proteoglycan, plays a role in cell growth and differentiation. Mutations of the GPC3 gene are responsible for Simpson-Golabi-Behmel syndrome, which is characterized by anomalies of postnatal overgrowth and an increased risk of developing pediatric malignancies, mostly Wilms tumor and liver cancer. In order to understand the possible role of GPC3 in renal development and Wilms tumor formation, we analyzed messenger RNA (mRNA) and protein levels of GPC3 in sporadic Wilms tumors and compared it to normal kidneys and other common renal epithelial tumors. By using Affymetrix HGU133 oligonucleotide gene expression microarray data from 191 renal tumors and 12 normal kidneys, we found significant overexpression of GPC3 in Wilms tumors (p < 0.01), with 3.5-fold higher expression in comparison to normal kidneys and 6.5-fold higher than any type of renal tumors. The GPC3 gene product in Wilms tumor was further evaluated by immunohistochemistry and quantified by an automated image analysis. Cytoplasmic and membranous GPC3 immunoreactivity was present in 77 % of primary Wilms tumors (23/30), 93 % of metastatic Wilms tumors (13/14), 50 % of metanephric adenomas (4/8), 33 % of congenital mesoblastic nephromas (2/6), 100 % of nephrogenic rests (11/11), and 100 % of fetal kidneys (5/5). GPC3 staining was predominantly identified in blastemal and epithelial components of Wilms tumors, similar to that of fetal non-neoplastic kidney. All adult renal tumors (n = 60) and normal kidneys (n = 15) were GPC3 negative. These findings suggest the utility of GPC3 in differential diagnosis and follow-up of Wilms tumors. Our data also indicate that GPC3 is an oncofetal protein with a potential therapeutic value.
磷脂酰肌醇蛋白聚糖3(GPC3)是一种硫酸乙酰肝素蛋白聚糖,在细胞生长和分化中发挥作用。GPC3基因的突变会导致辛普森-戈拉比-贝梅尔综合征,其特征为出生后过度生长异常以及儿童期恶性肿瘤(主要是肾母细胞瘤和肝癌)发病风险增加。为了了解GPC3在肾脏发育和肾母细胞瘤形成中的可能作用,我们分析了散发性肾母细胞瘤中GPC3的信使核糖核酸(mRNA)和蛋白质水平,并将其与正常肾脏及其他常见肾上皮肿瘤进行比较。通过使用来自191例肾肿瘤和12例正常肾脏的Affymetrix HGU133寡核苷酸基因表达微阵列数据,我们发现肾母细胞瘤中GPC3显著过表达(p < 0.01),与正常肾脏相比表达量高3.5倍,比任何类型的肾肿瘤高6.5倍。通过免疫组织化学进一步评估肾母细胞瘤中的GPC3基因产物,并通过自动图像分析进行定量。77%的原发性肾母细胞瘤(23/30)、93%的转移性肾母细胞瘤(13/14)、50%的后肾腺瘤(4/8)、33%的先天性中胚层肾瘤(2/6)、100%的肾源性剩余(11/11)以及100%的胎儿肾脏(5/5)中存在细胞质和膜性GPC3免疫反应性。GPC3染色主要在肾母细胞瘤的胚芽和上皮成分中发现,类似于胎儿非肿瘤性肾脏。所有成人肾肿瘤(n = 60)和正常肾脏(n = 15)均为GPC3阴性。这些发现表明GPC3在肾母细胞瘤的鉴别诊断和随访中具有实用价值。我们的数据还表明GPC3是一种具有潜在治疗价值的癌胚蛋白。