Wichmann Henri, Güttler Antje, Bache Matthias, Taubert Helge, Rot Swetlana, Kessler Jacqueline, Eckert Alexander W, Kappler Matthias, Vordermark Dirk
Department of Radiotherapy, Martin-Luther-University Halle-Wittenberg, Halle, Germany,
Strahlenther Onkol. 2015 Feb;191(2):180-91. doi: 10.1007/s00066-014-0743-9. Epub 2014 Aug 27.
The epidermal growth factor receptors, EGFR (HER1) and HER2, have proven prognostic relevance in a variety of human malignancies and both are functionally involved in the molecular pathogenesis of malignant gliomas.
We selectively inhibited EGFR and HER2 in glioblastoma cell lines via EGFR- and HER2-specific siRNAs and through the binding of the therapeutic antibodies cetuximab and trastuzumab. The expression of EGFR and HER2 was verified by real-time PCR and western blot analyses. We examined the growth rate, cell cycle distribution, cell migration, clonogenic survival, and radiosensitivity of U251MG and LN-229 glioblastoma cell lines to determine the physiological and cell biological effects of EGFR and HER2 targeting.
EGFR and HER2 targeting using the therapeutic antibodies cetuximab and trastuzumab had no effect on cellular growth rate, cell cycle distribution, cell migration, clonogenic survival, and radiosensitivity in the cell lines U251 and LN-229. In contrast, siRNA knock-down of EGFR and HER2, reduced the growth rate by 40-65 %. The knock-down of EGFR did not change the cell migration rate in the cell lines U251 and LN-229. However, knock-down of HER2 reduced the cell migration rate by 50 %. Radiobiological analysis revealed that EGFR knock-down induced no radiosensitization in U251MG and LN-229 cells. However, the knock-down of HER2 induced radiosensitization in U251MG cells.
The epidermal growth factor receptor HER2 is a promising anti-tumor target for the therapy of glioblastoma. HER2 targeting may represent a promising strategy to induce cell physiological and radiobiological anti-tumor effects in glioblastoma.
表皮生长因子受体EGFR（HER1）和HER2已被证实在多种人类恶性肿瘤中具有预后相关性，且二者均在恶性胶质瘤的分子发病机制中发挥功能作用。
我们通过EGFR和HER2特异性小干扰RNA（siRNA）以及治疗性抗体西妥昔单抗和曲妥珠单抗的结合，选择性抑制胶质母细胞瘤细胞系中的EGFR和HER2。通过实时聚合酶链反应（PCR）和蛋白质免疫印迹分析验证EGFR和HER2的表达。我们检测了U251MG和LN - 229胶质母细胞瘤细胞系的生长速率、细胞周期分布、细胞迁移、克隆形成存活率和放射敏感性，以确定靶向EGFR和HER2的生理和细胞生物学效应。
使用治疗性抗体西妥昔单抗和曲妥珠单抗靶向EGFR和HER2对U251和LN - 229细胞系的细胞生长速率、细胞周期分布、细胞迁移、克隆形成存活率和放射敏感性均无影响。相比之下，siRNA敲低EGFR和HER2可使生长速率降低40 - 65%。敲低EGFR并未改变U251和LN - 229细胞系中的细胞迁移速率。然而，敲低HER2可使细胞迁移速率降低50%。放射生物学分析显示，敲低EGFR在U251MG和LN - 229细胞中未诱导放射增敏作用。然而，敲低HER2在U251MG细胞中诱导了放射增敏作用。
表皮生长因子受体HER2是胶质母细胞瘤治疗中一个有前景的抗肿瘤靶点。靶向HER2可能是在胶质母细胞瘤中诱导细胞生理和放射生物学抗肿瘤效应的一种有前景的策略。
