目的 探讨膀胱癌患者CDCA8基因的表达情况和CDCA8基因与膀胱癌的临床病理相关性及预后相关性,预测CDCA8是如何推动膀胱癌发生、发展及其机制。方法 从NCBI(National Center for Biotechnology Information)的GEO数据库中下载膀胱癌基因表达数据GSE13507,采用非配对t检验分析CDCA8在膀胱癌中的表达情况,χ2检验分析CDCA8表达与膀胱癌患者临床病理指标的相关性,Log-rank检验用于预后生存分析;利用基因富集分析(GSEA)方法,分析CDCA8高表达样本的富集基因及受CDCA8调控的相关基因。结果 膀胱癌中CDCA8表达水平明显高于正常膀胱组(8.87±0.08 vs 7.47±0.07, P<0.0001);CDCA8的表达与膀胱癌患者的年龄(P=0.027)、性别(P=0.04)及膀胱癌的疾病进展(P=0.001)、T分期(P<0.0001)、N分期(P=0.013)、不同分级(P<0.0001)密切相关;CDCA8高表达组膀胱癌患者的肿瘤特异性生存期明显短于CDCA8低表达组(P<0.0001, HR=0.5177, 95% CI: 13.40~18.10),且CDCA8高表达组膀胱癌患者的总生存期亦短于CDCA8低表达组(P<0.0001, HR=0.09906, 95% CI: 5.971~16.38);CDCA8可能调控与精子形成、G2M检查点、E2F信号通路、未折叠蛋白反应、MYC信号通路、MTORC1信号通路、有丝分裂纺锤体形成、PI3K/AKT/mTOR通路、胆固醇平衡、糖酵解相关的基因集。结论 CDCA8在膀胱癌组织中显著高表达,且与膀胱癌的恶性程度和发生进展相关,高表达CDCA8的膀胱癌患者临床预后更差,可能作为潜在的判断膀胱癌患者疾病进展的标志物和治疗膀胱癌的靶标。
Abstract
Objective To investigate the expression of CDCA8 in bladder cancer (BC), to clarify the relationships between CDCA8 expressions and clinicopathological characteristics of BC and the prognostic value of CDCA8 in BC, and to evaluate the mechanism of CDCA8 in BC.Methods The bladder cancer sample expression profiles including CDCA8 expression data and its clinical information were downloaded from GEO datasets. The expression of CDCA8 in bladder cancer was analyzed by non-paired t test. The correlations between CDCA8 gene expression and the clinicopathologic features were analyzed by Chi-square test. Overall survival and specific survival were analyzed using Log-rank method. GSEA(gene set enrichment analysis)was conducted to explore the associated gene sets regulated by CDCA8.Results The expression of CDCA8 was up-regulated in BC (8.870±0.08281 vs 7.472±0.07035, P<0.0001). CDCA8 expression was significantly associated with age(P=0.027), gender(P=0.04), progression(P=0.001),T stage(P<0.0001), N stage(P=0.013)and grade(P<0.0001). Higher expressions of CDCA8 predicted both poor specific survival in BC(P<0.0001, HR= 0.5177, 95% CI: 13.40-18.10) and poor overall survival in BC(P<0.0001, HR=0.09906, 95% CI: 5.971-16.38). The Results of GSEA indicated that CDCA8 regulated gene sets associated with spermatogenesis, G2M checkpoint, E2F targets, Myc targets, mTORC1 signaling, mitotic spindle angiogenesis, PI3K/AKT/mTOR signaling, cholesterol homeostasis and glycolysis.Conclusions CDCA8 is highly expressed in BC, correlated with worse clinicopathological features and acts as a prognostic marker and target in the diagnosis and treatment of patients with BC.
关键词
膀胱癌 /
CDCA8 /
临床意义
Key words
bladder cancer /
CDCA8 /
clinical significance
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参考文献
[1] 司马晋,张保,艾青,等. 过表达Numb基因对人膀胱癌5637细胞周期和增殖的影响[J]. 肿瘤预防与治疗, 2016, 29(1):1-4.
[2] 单广夷,付成,陈昂,等. 雷帕霉素对膀胱癌5637细胞增殖及细胞周期的影响[J]. 中国医科大学学报, 2015, 44(3):230-233.
[3] 李雪玲,丁明彦,孙荣泽,等. 利用GEO公共数据集分析CHAF1A在肿瘤中的表达及临床意义[J]. 肿瘤, 2014, 34(7): 642-650.
[4] Yan H, Li Z, Shen Q, et al. Aberrant expression of cell cycle and material metabolism related genes contributes to hepatocellular carcinoma occurrence[J]. Pathol Res Pract, 2017, 213(4): 316-321.
[5] Horst A V D, Lens S M A. Cell division: control of the chromosomal passenger complex in time and space[J]. Chromosoma, 2014, 123(1/2): 25-42.
[6] Carmena M, Wheelock M, Funabiki H, et al. The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis[J]. Nat Rev Mol Cell Biol, 2012, 13(12):789-803.
[7] 戴灿. 细胞分裂周期相关基因CDCA8启动子的功能研究[D].湖南:中南大学, 2010.05.
[8] 戴灿,潘艺,苗聪秀,等. 人类胚胎干细胞分化前后CDCA8基因启动子区甲基化状态的实验研究[J]. 激光生物学报,2010,19(2): 259-262.
[9] 杜娟, 林戈, 卢光琇. 人胚胎干细胞和分化细胞差别基因的筛选[J]. 遗传学报, 2004, 31(9): 956-962.
[10] Zhang Q, Lin G, Gu Y, et al. Borealin is differentially expressed in ES cells and is essential for the early development of embryonic cells[J]. Mol Biol Rep, 2009, 36(3): 603-609.
[11] 张路遥,黄辉星,曹立环,等. CDCA8和INCENP在肝细胞癌组织中的表达及其临床意义[J]. 中国肿瘤生物治疗杂志,2017,24(2):158-167.
[12] Kim W J,Kim E J,Kim S K,et al. Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer[J]. Mol Cancer, 2010, 9(1): 3.
[13] Lee JS,Leem SH,Lee SY,et al. Expression signature of E2F1 and its associated genes predict superficial to invasive progression of bladder tumors[J]. J Clin Oncol,2010,28(16):2660-2667.
[14] 卢广明,苏永权,梁宝坚,等. Ebp1在膀胱癌中的表达及其对细胞周期的作用[J]. 中华临床医师杂志,2012,6(16):4679-4682.
[15] Hanley M L, Yoo T Y, Sonnett M, et al. Chromosomal passenger complex hydrodynamics suggests chaperoning of the inactive state by nucleoplasmin/nucleophosmin[J]. Mol Biol Cell,2017,28(11):1444-1456.
[16] Walker M G.Drug target discovery by gene expression analysis: cell cycle genes[J].Curr Cancer Drug Tar,2001, 1(1):73-83.
[17] Hayama S, Daigo Y, Yamabuki T, et al. Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis[J]. Cancer Res, 2007, 67(9):4113-4122.
[18] Wang Y, Zhao Z, Bao X, et al. Borealin/Dasra B is overexpressed in colorectal cancers and contributes to proliferation of cancer cells[J]. Med Oncol,2014,31(11):248.
[19] Dai C, Miao C X, Xu X M, et al. Transcriptional activation of human CDCA8 gene regulated by transcription factor NF-Y in embryonic stem cells and cancer cells[J]. J Bio Che,2015,290(37):22423-22434.
[20] Chang J L, Chen T H, Wang C F, et al. Borealin/Dasra B is a cell cycle-regulated chromosomal passenger protein and its nuclear accumulation is linked to poor prognosis for human gastric cancer[J]. Exp Cell Res, 2006, 312(7):962-973.
[21] Kabisch M, Lorenzo B J, Dünnebier T, et al. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer[J]. Carcinogenesis, 2015, 36(2): 256-271.
[22] Adams M N, Burgess J T, He Y, et al. Expression of CDCA3 is a prognostic biomarker and potential therapeutic target in non-small cell lung cancer[J]. J Thorac Oncol, 2017, 12(7): 1071-1084.
[23] Ribeiro-Varandas E, Viegas W, Pereira H S, et al. Bisphenol A at concentrations found in human serum induces aneugenic effects in endothelial cells[J]. Mutat Res, 2013, 751(1): 27-33.
[24] Yue L, Li L, Li D, et al. High-throughput screening for Survivin and Borealin interaction inhibitors in hepatocellular carcinoma[J]. Biochem Biophys Res Commun, 2017, 484(3): 642-647.
基金
中央高校基本科研业务费专项资金资助(2042018kf0077); 武汉大学珞珈青年学者科研基金(351人才计划)
