Music Darija, Dahlrot Rikke Hedegaard, Hermansen Simon Kjær, Hjelmborg Jacob, de Stricker Karin, Hansen Steinbjørn, Kristensen Bjarne Winther
Department of Pathology, Odense University Hospital, J. B. Winsløws Vej 15, Odense C, Denmark.
Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, Odense C, Denmark.
J Neurooncol. 2016 Apr;127(2):381-9. doi: 10.1007/s11060-015-2050-4. Epub 2016 Jan 6.
High-grade gliomas have an aggressive clinical course and new clinical biomarkers and therapeutic targets are highly needed. WEE1 is a regulator of the G2 checkpoint in glioblastoma (GBM) cells. Inhibition of this kinase has, in experimental glioma studies, been suggested to enhance sensitivity to irradiation and temozolomide. However, expression level and prognostic potential of WEE1 protein in gliomas remain uninvestigated. In this study, glioma samples from 235 patients across all four WHO grades were analyzed by immunohistochemistry. Using image analysis, we calculated the area fraction of WEE1 positive nuclei. We found that WEE1 protein was localized in tumor cell nuclei and expressed in all glioma types and grades. Although WEE1 protein levels are higher in GBMs (mean 24.5%) relative to grade III (mean 14,0%, p < 0.05) and grade II (mean 6.8%, p < 0.001) gliomas, high WEE1 protein was associated with better survival in GBMs (p = 0.002). This was confirmed in multivariate analysis (HR 0.60, p = 0.003) even when adjusted for MGMT status (HR 0.60, p = 0.005). In conclusion, we report a nuclear expression of WEE1 protein in all glioma grades and types. The WEE1 positive nuclear area was correlated with malignancy grade but it was inversely associated with prognosis in GBM. Although WEE1 is a frequently occurring protein and has been proposed as a novel target in GBM, the role of WEE1 in glioma patient survival appears to be connected to the MGMT status and is more complex than previously anticipated.
高级别胶质瘤临床进程侵袭性强，因此迫切需要新的临床生物标志物和治疗靶点。WEE1是胶质母细胞瘤（GBM）细胞中G2检查点的调节因子。在实验性胶质瘤研究中，抑制这种激酶可增强对放疗和替莫唑胺的敏感性。然而，胶质瘤中WEE1蛋白的表达水平和预后潜力仍未得到研究。在本研究中，我们通过免疫组织化学分析了235例来自世界卫生组织所有四个级别的胶质瘤患者的样本。通过图像分析，我们计算了WEE1阳性细胞核的面积分数。我们发现WEE1蛋白定位于肿瘤细胞核中，在所有类型和级别的胶质瘤中均有表达。尽管相对于III级（平均14.0%）和II级（平均6.8%）胶质瘤，GBM中WEE1蛋白水平更高（平均24.5%，p<0.05），但GBM中高WEE1蛋白与更好的生存率相关（p=0.002）。多因素分析证实了这一点（HR 0.60，p=0.003），即使在调整MGMT状态后也是如此（HR 0.60，p=0.005）。总之，我们报道了WEE1蛋白在所有级别和类型的胶质瘤中的核表达。WEE1阳性核面积与恶性程度相关，但与GBM的预后呈负相关。尽管WEE1是一种常见蛋白，并已被提议作为GBM的新靶点，但WEE1在胶质瘤患者生存中的作用似乎与MGMT状态有关，且比之前预期的更为复杂。
