Cytoplasmic EBP50 and elevated PARP1 are unfavorable prognostic factors in ovarian clear cell carcinoma
Cytoplasmic EBP50 and elevated PARP1 are unfavorable prognostic factors in ovarian clear cell carcinoma
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胞浆EBP 50和PARP 1升高是卵巢透明细胞癌的不良预后因素
DOI：
10.1093/carcin/bgab070
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发表时间：
2021-07-29
期刊：
影响因子：
4.7
通讯作者：
Saegusa, Makoto
中科院分区：
文献类型：
--
作者：
Matsumoto, Toshihide;Yoki, Ako;Saegusa, Makoto
卵巢透明细胞癌（OCCC）患者经常复发，这很可能是由于化疗耐药性。我们使用鸟枪蛋白质组学分析，并确定上调ezrin结合磷蛋白50（EBP 50）在复发OCCC样本。胞质和/或核（Cyt/N），但不是膜，EBP 50免疫反应性显着高于复发OCCC相比，原发性肿瘤。OCCC细胞表达胞浆EBP 50显着不太容易顺铂（CDDP）诱导的细胞凋亡相比，细胞膜EBP 50表达。细胞质EBP 50敲低后的抗性消除伴随着XIAP和BCL 2的减少、BAX的增加和caspase-3切割的增加。我们发现，参与DNA损伤检测和修复的聚（ADP-核糖）聚合酶1（PARP 1）通过其PDZ 1结构域与EBP 50结合。CDDP处理的细胞表达胞质（但不是膜）EBP 50增加核PARP 1的表达，而敲低EBP 50细胞减少PARP 1的表达和活性后CDDP处理。最后，Cyt/N EBP 50和PARP 1评分高的OCCC患者的总体和无进展生存期预后最差。总之，我们的数据表明，细胞质EBP 50通过稳定PARP 1活性和调节XIAP/BCL 2/BAX轴来抑制细胞凋亡并促进OCCC存活。这可能会增加肿瘤复发的可能性，因此我们建议EBP 50和PARP 1的联合分析可能在OCCC预测和预后中具有很大的实用性。
Patients with ovarian clear cell carcinoma (OCCC) experience frequent recurrence, which is most likely due to chemoresistance. We used shotgun proteomics analysis and identified upregulation of ezrin-binding phosphoprotein 50 (EBP50) in recurrent OCCC samples. Cytoplasmic and/or nuclear (Cyt/N), but not membranous, EBP50 immunoreactivity was significantly higher in recurrent OCCC as compared with that of primary tumors. OCCC cells expressing cytoplasmic EBP50 were significantly less susceptible to cisplatin (CDDP)-induced apoptosis compared with cells expressing membranous EBP50. Abrogation of resistance following knockdown of cytoplasmic EBP50 was accompanied by decreased XIAP and BCL2, increased BAX and increased caspase-3 cleavage. We found that poly (ADP-ribose) polymerase1 (PARP1), which is involved in DNA damage detection and repair, binds to EBP50 through its PDZ1 domain. CDDP treatment of cells expressing cytoplasmic (but not membranous) EBP50 increased nuclear PARP1 expression, whereas knockdown of EBP50 cells decreased PARP1 expression and activity following CDDP treatment. Finally, OCCC patients with a combination of Cyt/N EBP50 and high PARP1 score had worst the prognosis for overall and progression-free survival. Together, our data suggest that cytoplasmic EBP50 inhibits apoptosis and promotes OCCC survival through stabilization of PARP1 activity and modulation of the XIAP/BCL2/BAX axis. This may increase the likelihood of tumor recurrence, and we therefore suggest a combined analysis for EBP50 and PARP1 may have great utility in OCCC prediction and prognosis.