Prognostic value of TOP2A in bladder urothelial carcinoma and potential molecular mechanisms
Prognostic value of TOP2A in bladder urothelial carcinoma and potential molecular mechanisms
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TOP2A在膀胱尿路上皮癌中的预后价值及潜在分子机制
DOI：
10.1186/s12885-019-5814-y
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发表时间：
2019-06-19
期刊：
影响因子：
3.8
通讯作者：
Xu, Chuanliang
中科院分区：
文献类型：
--
作者：
Zeng, Shuxiong;Liu, Anwei;Xu, Chuanliang
背景膀胱尿路上皮癌（bladder urothelial carcinoma，BLCA）患者的预后差异很大，传统的病理学预测指标通常不足以预测BLCA的异质性。方法采用RNA测序、真实的时间定量聚合酶链反应和免疫组化方法分别检测10例、40例和209例BLCA组织中TOP2A的表达水平。对公共数据库进行了分析以进行验证。通过细胞增殖、迁移、侵袭实验来探讨TOP2A在BLCA中的潜在功能。流式细胞仪检测细胞周期和凋亡。单变量和多变量的考克斯回归模型进行识别的独立危险因素的预后BLCA.ResultsWe发现TOP2A是显着上调BLCA样本，特别是高级别和先进的阶段肿瘤，与匹配的正常上皮组织相比。单变量考克斯回归分析显示TOP2A高表达与肿瘤特异性、无进展和无复发生存率显著相关，但在多变量模型中并非独立于临床特征。TOP2A基因的敲除可显著抑制BLCA细胞和非癌尿路上皮细胞的增殖。此外，BLCA细胞的迁移和侵袭能力被强烈抑制后，TOP2A敲低。流式细胞仪检测显示，TOP2A具有抗凋亡作用，敲低TOP2A可诱导J82细胞对阿霉素产生耐药性。此外，TOP2A对BLCA细胞的增殖、侵袭和存活具有重要的功能。
BackgroundThe prognosis of bladder urothelial carcinoma (BLCA) varies greatly among patients, and conventional pathological predictors are generally inadequate and often inaccurate to predict the heterogeneous behavior of BLCA. This study aims to investigate the prognostic value and function of TOP2A in BLCA.MethodsTOP2A expression level was examined by RNA-sequencing, quantitative real time polymerase chain reaction and immunohistochemistry from 10, 40 and 209 BLCA samples, respectively. Public databases were analyzed for validation. Cell proliferation, migration, invasion assays were performed to explore potential functions of TOP2A in BLCA. Flow cytometry was performed for cell cycle and apoptosis analysis. Univariable and multivariable Cox regression models were performed to identify independent risk factors for the prognosis of BLCA.ResultsWe found TOP2A was significantly upregulated in BLCA samples, especially for high-grade and advanced stage tumors, compared with matched normal epithelial tissue. Univariable COX regression analysis revealed high TOP2A expression was significantly associated with poorer cancer-specific, progression-free and recurrence-free survival, but not independently of clinical characteristics in the multivariable models. Knockdown of TOP2A remarkably inhibited the proliferation of BLCA cells and non-cancerous urothelial cells. Furthermore, migration and invasion capacity of BLCA cells were strongly suppressed after TOP2A knockdown. Moreover, flow cytometry suggested TOP2A had anti-apoptotic function, and knockdown of TOP2A could induce resistance to doxorubicin in J82 cells.ConclusionsIn our study, TOP2A was overexpressed in BLCA and could serve as a prognostic biomarker for BLCA. Moreover, TOP2A is functionally important for the proliferation, invasion and survival of BLCA cells.