Comprehensive bioinformatics analysis of the expression, prognostic value, and immune infiltration of chromobox family members in cervical cancer

Document Type : Original Article


1 Department of Gynaecology, SSL Central Hospital of Dongguan, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China

2 Department of Gynaecology, Shixing Maternal and Child Health Hospital, Shaoguan, Guangdong, China



Objective(s): Cervical cancer (CC) is the fourth most prevalent type of cancer in women worldwide and it is considered the leading cause of tumor-related death and malignancy. As part of complexes involved in epigenetic control, the proteins of the chromobox (CBX) family have been found to have a role in the growth of malignancies by preventing differentiation and increasing proliferation. Here, by a thorough investigation, we investigated the expression, prognostic significance, and immune infiltration of CBX in patients with CC. 
Materials and Methods: Differential expression, clinicopathological parameters, immune cell infiltration, enrichment analysis, genetic alteration, and prognostic value of CBXs in patients with CC were examined using TIMER, Metascape, STRING, GeneMANIA, cBioPortal, UALCAN, The Human Protein Atlas, Gene Expression Profiling Interactive Analysis (GEPIA), and Oncomine. 
Results: In CC tissues, CBX 2/3/4/5 and CBX 8 expression levels were considerably higher, whereas CBX 6/7 expression levels were lower. In CC, the CBX 5/6/8 promoters have elevated levels of methylation. The expression of CBX 2/6/8 and the pathological stage were connected. A 37% mutation rate of the differentially expressed CBX genes was observed. Also, there was a strong correlation of the CBXs expression with immune cell infiltration, such as T CD4+ cells, macrophages, neutrophils, B cells, T CD8+ cells, and dendritic cells. 
Conclusion: The investigation discovered that members of the CBXs family may be therapeutic targets for CC patients and may play significant roles in the development of CC tumors.


1. Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet 2019;393:169-182.
2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin 2021;71:7-33.
3. Ramachandran D, Dörk T. Genomic risk factors for cervical cancer. Cancers 2021;13:5137.
4. Lee J, Song Y, Soh EY. Prognostic significance of the number of metastatic lymph nodes to stratify the risk of recurrence. World J Surg 2014;38:858-862.
5. Ma RG, Zhang Y, Sun TT, Cheng B. Epigenetic regulation by polycomb group complexes: focus on roles of CBX proteins. J Zhejiang Univ Sci B 2014;15:412-428.
6. Wotton D, Merrill JC. Pc2 and SUMOylation. Biochem Soc Trans 2007;35:1401-1404.
7. Li Q, Pan Y, Cao Z, Zhao S. Comprehensive analysis of prognostic value and immune infiltration of chromobox family members in colorectal cancer. Front Oncol 2020;10:582667.
8. Zeng JS, Zhang ZD, Pei L, Bai ZZ, Yang Y, Yang H, et al. CBX4 exhibits oncogenic activities in breast cancer via Notch1 signaling. Int J Biochem Cell Biol 2018;95:1-8.
9. Wang X, Li L, Wu Y, Zhang R, Zhang M, Liao D, et al. CBX4 suppresses metastasis via recruitment of HDAC3 to the Runx2 promoter in colorectal carcinoma. Cancer Res 2016;76:7277-7289.
10. Li J, Ouyang T, Li M, Hong T, Alriashy M, Meng W, et al. CBX7 is dualistic in cancer progression based on its function and molecular interactions. Front Genet 2021;12:740794.
11. Li R, Yan Q, Tian P, Wang Y, Wang J, Tao N, et al. CBX7 Inhibits cell growth and motility and induces apoptosis in cervical cancer cells. Mol Ther Oncolytics 2019;15:108-116.
12. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, et al. ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia 2004;6:1-6.
13. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 2017;45:W98-W102.
14. Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK, et al. UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 2017;19:649-658.
15. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013;6:pl1.
16. Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, et al. The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res 2010;38:W214-220.
17. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019;47:D607-D613.
18. Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res 2017;77:e108-e110.
19. Asplund A, Edqvist PH, Schwenk JM, Pontén F. Antibodies for profiling the human proteome-The Human Protein Atlas as a resource for cancer research. Proteomics 2012;12:2067-2077.
20. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019;10:1523.
21. Yang YF, Pan YH, Tian QH, Wu DC, Su SG. CBX1 indicates poor outcomes and exerts oncogenic activity in hepatocellular carcinoma. Transl Oncol 2018;11:1110-1118.
22. Jangal M, Lebeau B, Witcher M. Beyond EZH2: Is the polycomb protein CBX2 an emerging target for anti-cancer therapy? Expert Opin Ther Targets 2019;23:565-578.
23. Wang B, Huang M, Wang X, Tseng Y, Luo F, Liu J. CBX2 expression in colorectal mucosa-adenoma-adenocarcinoma sequence. J Coll Physicians Surg Pak 2021;31:1051-1056.
24. Chen WY, Zhang XY, Liu T, Liu Y, Zhao YS, Pang D. Chromobox homolog 2 protein: A novel biomarker for predicting prognosis and Taxol sensitivity in patients with breast cancer. Oncol Lett 2017;13:1149-1156.
25. Lin H, Zhao X, Xia L, Lian J, You J. Clinicopathological and Prognostic Significance of CBX3 Expression in Human Cancer: a Systematic Review and Meta-analysis. Dis Markers 2020;2020:2412741.
26. Jiang N, Niu G, Pan YH, Pan W, Zhang MF, Zhang CZ, et al. CBX4 transcriptionally suppresses KLF6 via interaction with HDAC1 to exert oncogenic activities in clear cell renal cell carcinoma. EBioMedicine 2020;53:102692.
27. Wang Z, Fang Z, Chen G, Liu B, Xu J, Li F, et al. Chromobox 4 facilitates tumorigenesis of lung adenocarcinoma through the Wnt/β-catenin pathway. Neoplasia 2021;23:222-233.
28. Jiao HK, Xu Y, Li J, Wang W, Mei Z, Long XD, et al. Prognostic significance of Cbx4 expression and its beneficial effect for transarterial chemoembolization in hepatocellular carcinoma. Cell Death Dis 2015;6:e1689.
29. Wu C, Zhang J. Long non-conding RNA LOXL1-AS1 sponges miR-589-5p to up-regulate CBX5 expression in renal cell carcinoma. Biosci Rep 2020;40: BSR2020021.
30. Deng H, Guan X, Gong L, Zeng J, Zhang H, Chen MY, et al. CBX6 is negatively regulated by EZH2 and plays a potential tumor suppressor role in breast cancer. Sci Rep 2019;9:197.
31. Vad-Nielsen J, Jakobsen KR, Daugaard TF, Thomsen R, Brügmann A, Sørensen BS, et al. Regulatory dissection of the CBX5 and hnRNPA1 bi-directional promoter in human breast cancer cells reveals novel transcript variants differentially associated with HP1α down-regulation in metastatic cells. BMC cancer 2016;16:32.
32. Zheng H, Jiang WH, Tian T, Tan HS, Chen Y, Qiao GL, et al. CBX6 overexpression contributes to tumor progression and is predictive of a poor prognosis in hepatocellular carcinoma. Oncotarget 2017;8:18872-18884.
33. Tian P, Zhang C, Ma C, Ding L, Tao N, Ning L, et al. Decreased chromobox homologue 7 expression is associated with epithelial-mesenchymal transition and poor prognosis in cervical cancer. Open Med (Wars) 2021;16:410-418.
34. Zhou H, Li A, Li C, Wu M, Jin D, Shui M. The co-expression of CBX8 and PD-L1 and prognostic value in cervical cancer. Medicine 2021;100:e27056.