Research Paper Advance Articles

Integrated analysis and validation of the TRIM28-H2AX-CDK4 diagnostic model assists to predict the progression of HCC

Qifei Tian1, *, , Guofang Lu2,3, *, , Ying Ma4, *, , Lingling Ma1, , Yulong Shang2, , Ni Guo1, , Yan Huang5, , Lin Zhu4, , Rui Du6, ,

  • 1 Department of Gastroenterology, Dongying People’s Hospital, Dongying, Shandong 257091, China
  • 2 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, China
  • 3 Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi’an 710032, China
  • 4 Department of Gastroenterology, 941 Hospital of PLA, Xining, Qinghai 810007, China
  • 5 Department of Critical Medicine, 942 Hospital of PLA, Yin Chuan, Ning Xia, China
  • 6 Institute for Biomedical Sciences of Pain, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China
* Equal contribution

Received: July 7, 2023       Accepted: October 3, 2023       Published: October 20, 2023
How to Cite

Copyright: © 2023 Tian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality in the world. However, identifying key genes that can be exploited for the effective diagnosis and management of HCC remains difficult. The study aims to examine the prognostic and diagnostic value of TRIM28-H2AX-CDK4 axis in HCC. Analysis in TCGA, GSEA and Gene expression profiling interactive analysis online tools were performed to explore the expression profiles of TRIM28, H2AX and CDK4. Data demonstrating the correlation between TRIM28 expression levels and immune infiltration states or the expression of genes associated with immune checkpoints genes were exacted from TCGA and TIMER. Genetic alteration and enrichment analysis were performed using the cBioPortal and GEPIA2 tools. Finally, the expression of these proteins in HCC was then examined and validated in an independent cohort using immunohistochemistry. TRIM28 alteration exhibited co-occurrence instead of mutual exclusivity with a large number of immune checkpoint components and tumor-infiltrating immune cells, especially B cells, were found to serve roles in patients with HCC with different TRIM28 expression levels. Higher expression levels of TRIM28, H2AX and CDK4 were associated with a poorer prognosis and recurrence in patients with HCC according to TCGA, which was validated further in an independent cohort of patients with HCC. Area under curve revealed the superior predictive power of applying this three-gene signatures in this validation cohort. The diagnostic model based on this TRIM28-H2AX-CDK4 signature is efficient and provides a novel strategy for the clinical management of HCC.


HCC: Hepatocellular carcinoma; TRIM28: Tripartite motif containing 28; TCGA: The Cancer Genome Atlas; H2AX: H2A histone family member X; CDK4: Cyclin-dependent kinase 4; PTMs: Post-translational modifications; TRIM: Tripartite motif; GSEA: Gene Set Enrichment Analysis; GEPIA2: Gene expression profiling interactive analysis, version 2; TIMER: Tumor Immune Estimation Resource; OS: Overall survival; RFS: Relapse-free survival; PFS: Progression-free survival; ROC: Receiver Operating Characteristic; PD-1: Programmed cell death protein-1; CTLA-4: Cytotoxic T lymphocyte antigen 4; TIM3: T cell immunoglobulin and mucin domain-containing-3; TIGIT: T cell immunoreceptor with Ig and ITIM domains; KLRC1: Killer cell lectin like receptor C1; PD-L1: Programmed death-ligand; TME: Tumor microenvironment; PIAS: Protein inhibitor of activated STAT.