CCNB1、PTTG1和CBX3在肝细胞肝癌中的表达及其在患者预后评估中的价值

doi:10.3969/j.issn.1673-8640.2025.04.004

检验医学 ›› 2025, Vol. 40 ›› Issue (4): 331-337.DOI: 10.3969/j.issn.1673-8640.2025.04.004

• 肝癌新标志物基础研究和临床应用专题 • 上一篇下一篇

CCNB1、PTTG1和CBX3在肝细胞肝癌中的表达及其在患者预后评估中的价值

朱晶¹, 张如霖², 伍均³()

1.上海交通大学医学院附属第一人民医院输血科，上海 200080
2.上海交通大学医学院附属第一人民医院检验科，上海 200080
3.上海交通大学医学院附属第一人民医院嘉定医院检验科，上海 201812

收稿日期:2024-09-26 修回日期:2025-01-14 出版日期:2025-04-30 发布日期:2025-05-08
通讯作者: 伍均，E-mail：jun.wu@shsmu.edu.cn。
作者简介:朱晶，男，1991年生，硕士，初级检验师，主要从事肝癌分子标志物研究；张如霖，男，1986年生，硕士，副主任技师，主要从事肝癌发病机制研究。朱晶和张如霖对本研究具有同等贡献，并列为第一作者。
基金资助:
上海市嘉定区卫生系统重点学科建设资助项目(XK202405)

Expressions of CCNB1，PTTG1 and CBX3 in hepatocellular carcinoma and their roles in prognostic assessment

ZHU Jing¹, ZHANG Rulin², WU Jun³()

1. Department of Blood Transfusion，Shanghai General Hospital，Shanghai Jiaotong University School of Medicine，Shanghai 200080，China
2. Department of Clinical Laboratory，Shanghai General Hospital，Shanghai Jiaotong University School of Medicine，Shanghai 200080，China
3. Department of Clinical Laboratory，Shanghai General Hospital Jiading Branch，Shanghai Jiaotong University School of Medicine，Shanghai 201812，China

Received:2024-09-26 Revised:2025-01-14 Online:2025-04-30 Published:2025-05-08

摘要/Abstract

摘要：

目的探讨细胞周期蛋白B1（CCNB1）、垂体肿瘤转化蛋白1（PTTG1）和染色框同源物3（CBX3）在肝细胞肝癌（HCC）中的表达情况，及其在患者预后评估中的价值。方法选取2007年1月—2008年12月上海交通大学医学院附属第一人民医院HCC患者94例。从癌症基因组图谱计划（TCGA）数据库中获取与DNA损伤应答相关的差异表达基因（DRDEG），通过基因集变异分析（GSVA）筛选出与DRDEG相关的前50个通路，并通过共表达分析构建潜在的调控网络。采用免疫印迹法检测不同HCC细胞系（Li-7、Huh7、HepG2、PLCPRF5、Hep3B）、正常人肝细胞系THLE-2和HCC患者癌组织、癌旁组织（距肿瘤边缘2~3 cm）中CCNB1、PTTG1和CBX3蛋白的表达情况。采用Kaplan-Meier生存曲线评估HCC患者的生存情况。采用Cox回归分析评估HCC患者总生存期缩短的危险因素。结果在构建的调控网络模型中，CCNB1、PTTG1和CBX3位于网络的核心位置。各HCC细胞系CCNB1蛋白相对表达量均高于THLE-2细胞（P<0.05）。Li-7细胞、Huh7细胞、HepG2细胞和Hep3B细胞CBX3蛋白相对表达量均高于THLE-2细胞（P<0.001）。Li-7细胞、Huh7细胞、HepG2细胞和PLCPRF5细胞PTTG1蛋白相对表达量均高于THLE-2细胞（P<0.001）。HCC患者癌组织中CCNB1、PTTG1和CBX3蛋白相对表达量均显著高于癌旁组织（P<0.001）。CCNB1、PTTG1和CBX3蛋白高表达（H-score≥150分）的HCC患者总生存期均显著短于低表达（H-score<150分）患者（P<0.001）。PTTG1、CBX3和CCNB1均是HCC患者总生存期缩短的危险因素（P<0.05）。结论 CCNB1、PTTG1和CBX3或可作为HCC的潜在治疗靶点和预后评估标志物。

关键词: 细胞周期蛋白B1, 垂体肿瘤转化蛋白1, 染色框同源物3, 肝细胞肝癌

Abstract:

Objective To investigate the expressions of cell cycle protein B1（CCNB1），pituitary tumor transforming gene 1（PTTG1） and chromobox homolog 3（CBX3） in hepatocellular carcinoma and to further study their roles in prognostic assessment.Methods A total of 94 patients with HCC from January 2007 to December 2008 were enrolled from Shanghai General Hospital of Shanghai Jiaotong University School of Medicine. DNA damage response related differentially expressed genes（DRDEG） were obtained from the Cancer Genome Atlas（TCGA） database，the top 50 pathways associated with DRDEG were screened by gene set variation analysis（GSVA），and potential regulatory networks were constructed by co-expression analysis. The expressions of CCNB1，PTTG1 and CBX3 proteins in different HCC cell lines（Li-7，Huh7，HepG2，PLCPRF5，Hep3B），normal human hepatocyte cell line THLE-2 and cancer and adjacent tissues（2-3 cm from tumor margin） of HCC patients were determined by immunoblotting. Kaplan-Meier survival curves were used to assess the survival of HCC patients. Cox regression analysis was used to assess the risk factors for shorter overall survival in HCC patients.Results In constructing the regulatory network model，CCNB1，PTTG1 and CBX3 were located at the core of the network. The relative expression of CCNB1 protein in each HCC cell was higher than that in THLE-2 cell（P<0.05）. The relative expressions of CBX3 protein in Li-7 cells，Huh7 cells，HepG2 cells and Hep3B cells were higher than those in THLE-2（P<0.001）. The relative expressions of PTTG1 protein in Li-7 cells，Huh7 cells，HepG2 cells and PLCPRF5 cells were higher than those in THLE-2 cells（P<0.001）. The relative expressions of CCNB1，PTTG1 and CBX3 proteins in cancer tissues were higher than those in adjacent tissues（P<0.001）. HCC patients with high expressions of CCNB1，PTTG1 and CBX3 proteins（H-score≥150） had a shorter overall survival than those of low expression HCC patients（H-score<150）（P<0.001），and PTTG1，CBX3 and CCNB1 were all risk factors for shorter overall survival in HCC patients（P<0.05）.Conclusions CCNB1，PTTG1 and CBX3 may be potential therapeutic targets and prognostic assessment markers for HCC.

Key words: Cell cycle protein B1, Pituitary tumor transforming gene 1, Chromobox homolog 3, Hepatocellular carcinoma

中图分类号:

R446.5

朱晶, 张如霖, 伍均. CCNB1、PTTG1和CBX3在肝细胞肝癌中的表达及其在患者预后评估中的价值[J]. 检验医学, 2025, 40(4): 331-337.

ZHU Jing, ZHANG Rulin, WU Jun. Expressions of CCNB1，PTTG1 and CBX3 in hepatocellular carcinoma and their roles in prognostic assessment[J]. Laboratory Medicine, 2025, 40(4): 331-337.

图/表 5

图1 DRDEG筛选结果注：（a）筛选出的50个DRDEG相关通路；（b）HCC组织和癌旁组织的差异表达基因；表达上调，表达下调；（c）调控网络模型图；转录因子， DRDEG，通路，免疫基因组， RPPA，免疫细胞；连接两点之间曲线的长短代表相互之间关联程度的强弱；红色曲线代表两点之间互为正向调控（P<0.000 1），蓝色曲线代表两点之间互为负向调控（P<0.000 1）。

图2 各HCC细胞系和THLE-2细胞CCNB1、PTTG1和CBX3蛋白表达的比较注：（a）各HCC细胞系和THLE-2细胞CCNB1、PTTG1和CBX3蛋白表达的免疫印迹图；（b）各HCC细胞系和THLE-2细胞CCNB1相对表达量比较；（c）各HCC细胞系和THLE-2细胞CBX3相对表达量比较；（d）各HCC细胞系和THLE-2细胞PTTG1相对表达量比较；与THLE-2细胞比较，*P<0.05、**P<0.001。

图3 HCC患者癌组织和癌旁组织CCNB1、PTTG1和CBX3蛋白表达的比较注：（a）癌组织和癌旁组织中CCNB1、PTTG1和CBX3蛋白表达的免疫印迹图；N为癌旁组织，T为癌组织；（b）癌组织和癌旁组织CCNB1蛋白表达的比较；（c）癌组织和癌旁组织CBX3蛋白表达的比较；（c）癌组织和癌旁组织PTTG1蛋白表达的比较。

图4 CCNB1、PTTG1和CBX3蛋白在细胞中的定位注：CCNB1和PTTG1蛋白主要定位于细胞质，CBX3蛋白定位于细胞核。

图5 不同CCNB1、PTTG1和CBX3蛋白表达HCC患者的Kaplan-Meier生存曲线分析和Cox回归分析注：（a）不同CCNB1蛋白表达HCC患者的Kaplan-Meier生存曲线；高表达，低表达；（b）不同PTTG1蛋白表达HCC患者的Kaplan-Meier生存曲线；高表达，低表达；（c）不同CBX3蛋白表达HCC患者的Kaplan-Meier生存曲线；高表达，低表达；（d）Cox回归分析的森林图；①HR为风险比（hazard ratio）；②CI为可信区间（confidence interval）。

参考文献 31

[1]	American Cancer Society. Cancer facts & figures 2022[EB/OL]. (2023-01-23)[2023-09-07]. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf.
[2]	SANGRO B, SAROBE P, HERVÁS-STUBBS S, et al. Advances in immunotherapy for hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(8):525-543. DOI PMID
[3]	FOERSTER F, GAIRING S J, ILYAS S I, et al. Emerging immunotherapy for HCC:a guide for hepatologists[J]. Hepatology, 2022, 75(6):1604-1626.
[4]	LLOVET J M, DE BAERE T, KULIK L, et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(5):293-313. DOI PMID
[5]	PILGER D, SEYMOUR L W, JACKSON S P. Interfaces between cellular responses to DNA damage and cancer immunotherapy[J]. Genes Dev, 2021, 35(9-10):602-618.
[6]	ZHANG T, ZHENG S, LIU Y, et al. DNA damage response and PD-1/PD-L1 pathway in ovarian cancer[J]. DNA Repair(Amst), 2021, 102:103112.
[7]	WANG C, TANG M, CHEN Z, et al. Genetic vulnerabilities upon inhibition of DNA damage response[J]. Nucleic Acids Res, 2021, 49(14):8214-8231. DOI PMID
[8]	BANERJEE D, LANGBERG K, ABBAS S, et al. A non-canonical,interferon-independent signaling activity of cGAMP triggers DNA damage response signaling[J]. Nat Commun, 2021, 12(1):6207.
[9]	CHATZIDOUKAKI O, GOULIELMAKI E, SCHUMACHER B, et al. DNA damage response and metabolic reprogramming in health and disease[J]. Trends Genet, 2020, 36(10):777-791. DOI PMID
[10]	BEDNARSKI J J, SLECKMAN B P. At the intersection of DNA damage and immune responses[J]. Nat Rev Immunol, 2019, 19(4):231-242. DOI PMID
[11]	SCHWEIZER M T, SIVAKUMAR S, TUKACHINSKY H, et al. Concordance of DNA repair gene mutations in paired primary prostate cancer samples and metastatic tissue or cell-free DNA[J]. JAMA Oncol, 2021, 7(9):1-5.
[12]	LULLI M, DEL COCO L, MELLO T, et al. DNA damage response protein CHK2 regulates metabolism in liver cancer[J]. Cancer Res, 2021, 81(11):2861-2873.
[13]	CHEN Y, WANG X, DENG X, et al. DNA damage repair status predicts opposite clinical prognosis immunotherapy and non-immunotherapy in hepatocellular carcinoma[J]. Front Immunol, 2021, 12:676922.
[14]	REISLÄNDER T, GROELLY F J, TARSOUNAS M. DNA damage and cancer immunotherapy:a STING in the tale[J]. Mol Cell, 2020, 80(1):21-28.
[15]	MOUW K W, GOLDBERG M S, KONSTANTINOPOULOS P A, et al. DNA damage and repair biomarkers of immunotherapy response[J]. Cancer Discov, 2017, 7(7):675-693. DOI PMID
[16]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249.
[17]	American Cancer Society. Key statistics about liver cancer[EB/OL].(2023-05-23)[2023-12-14]. https://www.cancer.net/cancer-types/liver-cancer/statistics.
[18]	ROTTE A, JIN J Y, LEMAIRE V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy[J]. Ann Oncol, 2018, 29(1):71-83. DOI PMID
[19]	TEO M Y, SEIER K, OSTROVNAYA I, et al. Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers[J]. J Clin Oncol, 2018, 36(17):1685-1694. DOI PMID
[20]	JEGGO P A, PEARL L H, CARR A M. DNA repair,genome stability and cancer:a historical perspective[J]. Nat Rev Cancer, 2016, 16(1):35-42.
[21]	HUANG R X, ZHOU P K. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer[J]. Signal Transduct Target Ther, 2020, 5(1):60.
[22]	ZHUANG L, YANG Z, MENG Z. Upregulation of BUB1B,CCNB1,CDC7,CDC20,and MCM3 in tumor tissues predicted worse overall survival and disease-free survival in hepatocellular carcinoma patients[J]. Biomed Res Int, 2018, 2018:7897346.
[23]	FANG Y, YU H, LIANG X, et al. Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer[J]. Cancer Biol Ther, 2014, 15(9):1268-1279. DOI PMID
[24]	FLORENSA R, BACHS O, AGELL N. ATM/ATR-independent inhibition of cyclin B accumulation in response to hydroxyurea in nontransformed cell lines is altered in tumour cell lines[J]. Oncogene, 2003, 22(51):8283-8292. DOI PMID
[25]	LIN X, YANG Y, GUO Y, et al. PTTG1 is involved in TNF-α-related hepatocellular carcinoma via the induction of c-myc[J]. Cancer Med, 2019, 8(12):5702-5715.
[26]	BOT C, PFEIFFER A, GIORDANO F, et al. Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage[J]. J Cell Sci, 2017, 130(6):1134-1146. DOI PMID
[27]	ZHONG X, KAN A, ZHANG W, et al. CBX3/HP1γ promotes tumor proliferation and predicts poor survival in hepatocellular carcinoma[J]. Aging(Albany NY), 2019, 11(15):5483-5497.
[28]	KIM S, BECKER J, BECHHEIM M, et al. Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes[J]. Nat Commun, 2014, 5:5236. DOI PMID
[29]	SUN M, HA N, PHAM D H, et al. Cbx3/HP1γ deficiency confers enhanced tumor-killing capacity on CD8⁺T cells[J]. Sci Rep, 2017, 7:42888.
[30]	LE P T, HA N, TRAN N K, et al. Targeting Cbx3/HP1γ induces LEF-1 and IL-21R to promote tumor-infiltrating CD8 T-cell persistence[J]. Front Immunol, 2021, 12:738958.
[31]	ZHANG H, CHEN W, FU X, et al. CBX3 promotes tumor proliferation by regulating G1/S phase via p21 downregulation and associates with poor prognosis in tongue squamous cell carcinoma[J]. Gene, 2018, 654:49-56. DOI PMID

CCNB1、PTTG1和CBX3在肝细胞肝癌中的表达及其在患者预后评估中的价值

Expressions of CCNB1，PTTG1 and CBX3 in hepatocellular carcinoma and their roles in prognostic assessment

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 5

参考文献 31

相关文章 15

编辑推荐

Metrics

[1]	田泽, 刘宏瑞, 司文喆. 外泌体微小RNA作为肝细胞肝癌生物标志物的研究进展[J]. 检验医学, 2025, 40(4): 317-323.
[2]	孙海青, 刘宁, 娄金丽, 于艳华. STIP1和AFP-L3联合检测在肝细胞肝癌诊断中的价值[J]. 检验医学, 2025, 40(4): 324-330.
[3]	王晓龙, 陈元斌. 血清CDC42与AFP阴性HCC患者临床病理特征和预后的相关性[J]. 检验医学, 2025, 40(3): 259-263.
[4]	刘洋, 何成山, 蒋秀娣, 陆志成. HBV PreS/S区基因突变诱导肝细胞内质网应激致肝细胞肝癌相关机制研究进展[J]. 检验医学, 2024, 39(12): 1229-1233.
[5]	中国康复医学会医学检验与康复专业委员会, 上海市医学会分子诊断专科分会, 上海市免疫学会肿瘤免疫分会, 上海中医药大学附属岳阳中西医结合医院, 上海市临床检验中心, 中国中西医结合学会检验医学专业委员会, 上海市抗癌协会检验医学专业委员会, 上海市抗癌协会肿瘤标志物专业委员会. 肝癌三项（AFP、AFP-L3%、DCP）与GALAD、类GALAD模型临床应用专家共识[J]. 检验医学, 2023, 38(7): 607-623.
[6]	陈文举, 周勇, 徐佳佳, 王攀. 血清外泌体miR-23b-3p和miR-4429诊断HCC的价值[J]. 检验医学, 2023, 38(7): 624-628.
[7]	孟俊, 王俊青, 费晓春, 顾志冬. 血浆外泌体circRNA诊断HCC联合检测模型的建立与验证[J]. 检验医学, 2022, 37(1): 1-10.
[8]	胡涛, 卢仁泉, 郭林. TK1检测在HCC辅助诊断及预后评估中的临床价值[J]. 检验医学, 2021, 36(9): 914-919.
[9]	包大伟, 黄建. CD133和ALDH1在肝细胞肝癌中的临床价值[J]. 检验医学, 2021, 36(9): 925-928.
[10]	程惠芬. 血清P-选择素、ICAM-1、IL-17A水平在HBV感染相关疾病中的临床价值[J]. 检验医学, 2021, 36(6): 646-649.
[11]	童林, 黄晨军, 高致远, 周军, 房萌, 肖潇, 何羽童, 洪松, 许敏凡, 朱飞飞, 高春芳. 基于临床常用检验项目的原发性肝细胞肝癌术前微血管侵犯诊断模型研究[J]. 检验医学, 2020, 35(8): 741-748.
[12]	金方方, 金子铮, 刘宁, 娄金丽. 肝细胞肝癌复发前后CD3高表达T淋巴细胞的变化[J]. 检验医学, 2020, 35(3): 209-213.
[13]	方子祥, 张骁, 陈岩, 吴棋, 邾国庆, 刘雅, 王佳谊, 孙奋勇, 俞蕾. TFCP2/YAP转录复合体调控蛋白CPE对肝细胞肝癌的诊断价值[J]. 检验医学, 2019, 34(2): 103-109.
[14]	唐洁, 杨渝伟, 王堃, 喻晶. 化学发光微粒子免疫法测定维生素K缺乏诱导蛋白成人参考区间的建立[J]. 检验医学, 2019, 34(12): 1072-1076.
[15]	尚璐, 张骁, 陈岩, 吴棋, 邾国庆, 刘雅, 王佳谊, 孙奋勇, 张蕾. Hippo/YAP信号通路调控蛋白ACAN作为新型肝细胞肝癌血清肿瘤标志物的研究[J]. 检验医学, 2019, 34(1): 60-66.