Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma.
Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma.
复制标题
HER2 和 HER4 共表达在儿童髓母细胞瘤中的预后意义。
作者：
R. Gilbertson;Robert H. Perry;P. Kelly;A. Pearson;J. Lunec
表皮生长因子受体（EGFR）家族的最近的体外研究揭示了复杂的信号相互作用，其涉及在体外细胞转化中协同的配体介导的异二聚体的产生。在一系列的70例儿童髓母细胞瘤患者中，我们使用免疫组织化学和蛋白质印迹分析来研究所有四种EGFR家族成员（EGFR，HER 2，HER 3和HER 4）和heregulin-alpha（HER 3和HER 4受体的配体）的表达模式。大多数病例表达两种或多种受体蛋白; 54%的病例共表达HER 2和HER 4受体。在31%的肿瘤中检测到配体heregulin-alpha的表达。为了研究共表达是否会导致受体异源二聚化，我们还对原发性肿瘤的蛋白质提取物进行了免疫沉淀分析，并证明了包括HER 2和HER 4之间的各种受体相互作用模式。在临床病理疾病特征的多变量25年生存分析中，没有个体受体或heregulin-alpha达到显著性。相比之下，当在多变量模型中一起考虑时，HER 2和HER 4的共表达表现出独立的预后意义（P = 0.006）。这些数据表明，HER 2-HER 4受体异源二聚化在这种疾病中具有特殊的生物学意义，并且该报告首次证明了EGFR家族异源二聚化在人类癌症中的潜在临床意义。最后，我们还分析了AP-2转录因子在恶性细胞中HER 2和HER 3基因转录的正调控中的表达，并揭示了AP-2表达不仅与HER 2和HER 3有关，而且与髓母细胞瘤原发性肿瘤中的HER 4水平有关。
Recent in vitro studies of the epidermal growth factor receptor (EGFR) family have revealed complex signaling interactions involving the production of ligand-mediated heterodimers synergistic for the transformation of cells in vitro. In a series of 70 patients with childhood medulloblastoma, we have used immunohistochemistry and Western blotting analysis to investigate the expression patterns of all four EGFR family members (EGFR, HER2, HER3, and HER4) and heregulin-alpha, a ligand for the HER3 and HER4 receptors. The majority of cases expressed two or more receptor proteins; coexpression of the HER2 and HER4 receptors occurred in 54%. Expression of the ligand heregulin-alpha was detected in 31% of tumors. To investigate whether coexpression results in receptor heterodimerization, we have also performed immunoprecipitation analysis of protein extracts from primary tumors, and we demonstrate various patterns of receptor interaction including between HER2 and HER4. In multivariate 25-year survival analysis with clinicopathological disease features, no individual receptor or heregulin-alpha achieved significance. In contrast, when considered together in the multivariate model, coexpression of HER2 and HER4 demonstrated independent prognostic significance (P = 0.006). These data suggest the hypothesis that HER2-HER4 receptor heterodimerization is of particular biological significance in this disease, and this report is the first to demonstrate potential clinical significance of EGFR family heterodimerization in human cancer. Finally, we have also analyzed expression of the AP-2 transcription factor implicated in the positive regulation of HER2 and HER3 gene transcription in malignant cells and reveal an association between AP-2 expression and not only HER2 and HER3, but also HER4 levels in medulloblastoma primary tumors.