背景:促凋亡蛋白和抗凋亡蛋白的平衡在调节细胞死亡中起着关键作用,这种微妙平衡的破坏可能会通过细胞凋亡的净减少而导致癌变。许多化疗策略直接或间接靶向凋亡途径。然而,之前尚未在子宫内膜透明细胞癌(CCC)中对凋亡相关蛋白进行过全面评估.本研究旨在确定9种凋亡相关蛋白在CCC发病机制中的意义,与非肿瘤性子宫内膜(NNE)相比,低级别和高级别子宫内膜子宫内膜样癌(LG-EEC,HG-EEC),子宫内膜浆液性癌(ESC)。
方法:6种抗凋亡蛋白(Bcl-2,Bcl-xL,cFLIPL,MCL-1幸存者,NFκB/p65)和三种促凋亡蛋白(Bax,caspase-3,caspase-8)通过免疫组织化学在49个CCC上进行评估,37LG-EEC,12HG-ECC,16ESC,和25NNE在组织微阵列中。通过自动图像捕获系统分配客观IHC评分。然后将评分与临床病理价值相互关联。
结果:最值得注意的是,CCC显示cFLIPL相对于ESC的表达显着降低,LG-EEC,HG-EEC,和NNE。CCC还显示相对于ESC,Caspase8和NF-κB/p65的表达显着降低,HG-EEC,NNE,但不是LG-EEC。相对于除Bcl-2的ESC和Bcl-xL的NNE外的所有组,Bcl-2和Bcl-xL在CCC中显示表达降低。关于表达水平,蛋白质之间没有显着相关性。在CCC组中,这些蛋白质都没有显示出与患者年龄有显著关联,子宫肌层浸润,最后阶段,淋巴管浸润,无病或总体生存率。
结论:我们对一组凋亡相关蛋白的表达和相关模式的分析表明,cFLIPL在CCC中的下调相对于几乎所有其他组织都是显著的,NNE,HG-EEC,和ESC。其他蛋白质,包括Caspase8、NF-κB/p65、Bcl-2和Bcl-xL也可能是显著的。CCC中凋亡相关蛋白的调节可能很重要,并且可以深入了解这种神秘的组织型中的化学抗性。然而,促凋亡和抗凋亡介质的异常下调表明,需要进一步的研究来阐明凋亡机制在CCC中的作用.
BACKGROUND: The balance of pro- and anti-apoptotic proteins plays a critical role in the regulation of cell death, and a disruption of this delicate balance may eventuate in carcinogenesis through a net reduction in apoptosis. Numerous chemotherapeutic strategies directly or indirectly target apoptotic pathways. However, a thorough assessment of apoptosis-related proteins has not previously been performed in endometrial clear cell carcinoma (CCC). This study aims to determine the significance of 9 apoptosis-related proteins in the pathogenesis of CCC as compared to non-neoplastic endometrium (NNE), low- and high-grade endometrial endometrioid carcinomas (LG-EEC, HG-EEC), and endometrial serous carcinoma (ESC).
METHODS: Expression of 6 anti-apoptotic proteins (Bcl-2, Bcl-xL, cFLIPL, MCL-1, survivin, NFκB/p65) and three pro-apoptotic proteins (Bax, caspase-3, caspase-8) was assessed by immunohistochemistry on 49 CCC, 37 LG-EEC, 12 HG-ECC, 16 ESC, and 25 NNE in a tissue microarray. Objective IHC scores were assigned by an automated image capture system. Scores were then correlated with clinicopathologic values and each other.
RESULTS: Most notably, CCC showed significantly reduced expression of cFLIPL relative to ESC, LG-EEC, HG-EEC, and NNE. CCC also showed significantly reduced expression of both Caspase 8 and NF-κB/p65 relative to ESC, HG-EEC, and NNE, but not LG-EEC. Bcl-2 and Bcl-xL showed reduced expression in CCC relative to all groups except ESC for Bcl-2 and NNE for Bcl-xL. There was no significant correlation between the proteins regarding expression levels. Within the CCC group, none of the proteins showed any significant association with patient age, myometrial invasion, final stage, lymphovascular invasion, disease-free or overall survival.
CONCLUSIONS: Our analysis of the expression and correlation patterns of a panel of apoptosis-related proteins suggests that the downregulation of cFLIPL in CCC is significant relative to almost all other tissues, NNE, HG-EEC, and ESC. Other proteins, including Caspase 8, NF-κB/p65, Bcl-2 and Bcl-xL may also be significant. The regulation of apoptosis-related proteins in CCC may be important and may provide insight into chemoresistance in this enigmatic histotype. However, the paradoxical downregulation of both pro- and anti-apoptotic mediators suggests that additional study is needed to clarify the role of apoptotic mechanisms in CCC.