Tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group proteins.
Tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group proteins.
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多梳蛋白证明上皮性卵巢癌复发中的肿瘤异质性
DOI：
10.2147/ott.s67570
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发表时间：
2014
影响因子：
4
通讯作者：
Shen K
中科院分区：
文献类型：
--
作者：
Gui T;Bai H;Zeng J;Zhong Z;Cao D;Cui Q;Chen J;Yang J;Shen K
目的探讨多梳蛋白(PcG)在上皮性卵巢癌复发中的异质性。方法构建包含来自同一患者的原发和复发卵巢肿瘤的组织芯片，以检测PcG蛋白的表达。对患者的无进展生存期(PFS)和总生存期(OS)进行临床病理参数和PcG蛋白表达的生存分析。从基因拷贝数和microRNA(MiRNA)图谱方面探讨了遗传和表观遗传的异质性。结果PcG蛋白在原发肿瘤和复发肿瘤中呈异质性表达(P<；0.05)。单因素生存分析显示，Bmi 1和EZH2在首发淋巴结转移癌中的高表达与PFS缩短显著相关(P=0.010，P=0.019)，在复发肿瘤中高表达与OS缩短显著相关(P=0.042，P=0.047)。重要的是，BMI1和EZH2的表达在多变量分析中提供了显著的独立预后参数(P<；0.05)。基因扩增并不总是与PcG蛋白的表达相一致。有8个miRNAs在复发肿瘤中表达下调，其中miR-298可能通过转录因子ILF3间接调节EZH2的表达。结论上皮性卵巢癌复发过程中存在肿瘤异质性，表现为PcG蛋白表达及潜在的遗传和表观遗传学改变。BMI1和EZH2的高表达是早期复发和较短OS的预测指标，与分级和化疗敏感性无关。EZH2和miR-298有望成为治疗复发性卵巢癌的新靶点。
Purpose To investigate tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group (PcG) proteins. Methods Tissue microarrays containing matched primary and recurrent ovarian tumors from the same patients were constructed for detection of PcG protein expression. Survival analyses of clinicopathological parameters and expression of PcG proteins were performed on progression-free survival (PFS) and overall survival (OS) of patients. Genetic and epigenetic heterogeneity was explored in aspects of gene copy number and microRNA (miRNA) profiling. Results PcG proteins were heterogeneously expressed in primary versus recurrent tumors (P<0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of intensive expression of BMI1 and EZH2 in first-onset lymph node metastases with shortened PFS was demonstrated (P=0.010, P=0.019); and a significant association of intensive expression of BMI1 and EZH2 in recurrent tumors with shortened OS was demonstrated (P=0.042, P=0.047). Importantly, BMI1 and EZH2 expression provided significant independent prognostic parameters in multivariate analyses (P<0.05). Gene amplification did not always coincide with PcG protein expression. Eight miRNAs were found to be downregulated in recurrent tumors, among which miR-298 might indirectly regulate the expression of EZH2 through transcription factor ILF3. Conclusion Tumor heterogeneity exists in the recurrence of epithelial ovarian cancer, manifested by PcG protein expression and underlying genetic and epigenetic alterations. Intensive expression of BMI1 and EZH2 are predictors of earlier relapse and shorter OS, independent of grade and chemotherapy sensitivity. EZH2 and miR-298 have great potential to be new targets for treatment of recurrent ovarian cancer.