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

doi:10.3969/j.issn.1673-8640.2025.04.004

Abstract

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

CLC Number:

R446.5

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.

Figures/Tables 5

References 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