Caspase-3 in glioma indicates an unfavorable prognosis by involving surrounding angiogenesis and tumor cell repopulation
Caspase-3 in glioma indicates an unfavorable prognosis by involving surrounding angiogenesis and tumor cell repopulation
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DOI：
10.1007/s11060-023-04339-x
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发表时间：
2023-05-17
影响因子：
3.9
通讯作者：
Cheng, Jin
中科院分区：
文献类型：
--
作者：
Feng, Xiao;Zhu, Feng;Cheng, Jin
目的目前缺乏有效的胶质瘤预后评估生物标志物。典型地，caspase-3充当“凋亡刽子手”。然而，其在胶质瘤中的预后作用和对预后的机制影响仍不清楚。MethodsWith胶质瘤组织微阵列，裂解的caspase-3的预后作用及其与血管生成的关系进行了探讨。接下来，通过分析来自CGGA的mRNA微阵列数据，研究CASP 3表达的预后作用以及CASP 3与胶质瘤血管生成和增殖的标志物之间的相关性。为了从生物学角度解释caspase-3在胶质瘤中的预后作用，采用体外细胞共培养模型研究caspase-3对周围血管生成和胶质瘤细胞再增殖的影响，该模型包括照射的U87细胞和未照射的萤火虫荧光素酶（Fluc）标记的HUVEC（HUVEC-Fluc）或U87（U87-Fluc）细胞。过度表达的显性负性caspase-3被用来抑制正常的caspase-3 activity.ResultsHigh水平的裂解caspase-3的表达与胶质瘤患者的生存预后差。在高水平裂解型caspase-3表达的患者中观察到更高的微血管密度。CGGA芯片数据挖掘显示，CASP 3在Karnofsky评分低、WHO分级高、恶性组织学亚型、野生型IDH的胶质瘤患者中表达增高。胶质瘤患者CASP 3表达越高，生存率越低。CASP 3高表达和IDH突变阴性的患者生存率最差。CASP 3与肿瘤血管生成和增殖标志物呈正相关。基于体外细胞共培养模型的后续数据显示，照射后的胶质瘤细胞中的caspase-3通过调节考克斯-2信号通路介导促血管生成和促进再生作用。使用胶质瘤组织微阵列，高水平的考克斯-2表达表明胶质瘤患者的生存结局较差。Caspase-3和考克斯-2高水平表达的胶质瘤患者的生存结局最差。caspase-3/考克斯-2信号通路的促血管生成和促进细胞增殖作用可能解释其不良预后作用，并为胶质瘤的治疗增敏和疗效预测提供新的见解。
AimEffective biomarkers for estimating glioma prognosis are deficient. Canonically, caspase-3 acts as an "apoptosis executioner". However, its prognostic role in glioma and mechanistic effects on prognosis remain unclear.MethodsWith glioma tissue microarrays, the prognostic roles of cleaved caspase-3 and its association with angiogenesis were explored. Next, by analyzing the mRNA microarray data from the CGGA, the prognostic role of CASP3 expression and correlations between CASP3 and markers of glioma angiogenesis and proliferation were investigated. To biologically interpret the prognostic role of caspase-3 in glioma, the influence of caspase-3 on surrounding angiogenesis and glioma cell repopulation was investigated with an in vitro cell co-culture model, which comprises irradiated U87 cells and un-irradiated firefly luciferase (Fluc)-labeled HUVEC (HUVEC-Fluc) or U87 (U87-Fluc) cells. The over-expressed dominant-negative caspase-3 was used to suppress normal caspase-3 activity.ResultsHigh levels of cleaved caspase-3 expression were associated with poor survival outcomes in glioma patients. Higher microvessel density was observed in patients with high levels of cleaved caspase-3 expression. By mining the microarray data in CGGA, it was revealed that higher CASP3 expression was found in glioma patients with lower Karnofsky Performance score, higher WHO grade, malignant histological subtype, wild-type IDH. Higher CASP3 expression indicated a worse survival rate in glioma patients. Patients with high CASP3 expression and negative IDH mutation showed the worst survival rate. Positive correlations were found between CASP3 and markers of tumor angiogenesis and proliferation. Subsequent data based on an in vitro cell co-culture model revealed that caspase-3 in irradiated glioma cells mediated pro-angiogenic and repopulation-promoting effects via regulating COX-2 signaling. With glioma tissue microarrays, high levels of COX-2 expression showed inferior survival outcomes in glioma patients. Glioma patients with high levels of cleaved caspase-3 and COX-2 expression showed the worst survival outcomes.ConclusionThis study innovatively identified an unfavorable prognostic role of caspase-3 in glioma. The pro-angiogenic and repopulation-prompting effects of caspase-3/COX-2 signaling may explain its unfavorable prognostic role and offer novel insights into therapy sensitization and curative effect prediction of glioma.