Expression and prognostic value of the WEE1 kinase in gliomas
Expression and prognostic value of the WEE1 kinase in gliomas
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DOI：
10.1007/s11060-015-2050-4
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发表时间：
2016-04-01
影响因子：
3.9
通讯作者：
Kristensen, Bjarne Winther
中科院分区：
文献类型：
--
作者：
Music, Darija;Dahlrot, Rikke Hedegaard;Kristensen, Bjarne Winther
高级别胶质瘤具有侵袭性的临床病程，迫切需要新的临床生物标记物和治疗靶点。Wee1是胶质母细胞瘤(GBM)细胞G2检查点的调节因子。在实验性的胶质瘤研究中，抑制该激酶被认为可以增强对辐射和替莫唑胺的敏感性。然而，WEE1蛋白在胶质瘤中的表达水平和预后潜力仍未被研究。在这项研究中，对来自所有四个WHO分级的235名患者的胶质瘤样本进行了免疫组织化学分析。用图像分析的方法计算了WEE1阳性核的面积分数。我们发现WEE1蛋白定位于肿瘤细胞核，在所有类型和分级的胶质瘤中均有表达。虽然WEE1蛋白在胶质瘤中的表达水平(平均24.5%)高于III级(平均14.0%，p<0.001)和II级(平均6.8%，p<0.001)，但WEE1蛋白的高表达与胶质瘤中较好的存活率有关(p=0.002)。在多变量分析中证实了这一点(HR0.60，p=0.003)，即使在调整了MGMT状态时(HR0.60，p=0.005)。总之，我们报告了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GBM的恶性程度呈正相关，与预后呈负相关。虽然WEE1是一种常见的蛋白，并已被认为是胶质瘤新的靶点，但WEE1在胶质瘤患者生存中的作用似乎与MGMT状态有关，并且比先前预期的更复杂。
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.