Abstract
Background
The ubiquitin proteasome has a major role in the development of many tumors. However, the prognostic importance of ubiquitin proteasome-system genes (UPSGs) in hepatocellular carcinoma (HCC) is not fully defined.
Methods
The TCGA and ICGC datasets were utilized to obtain transcriptional profiling data as well as clinicopathological information about HCC. The 3-UPSGs signature for the TCGA cohort was developed via univariate and LASSO Cox regression analyses. Differential expression of genes was demonstrated by qRT-PCR and immunohistochemistry (IHC). Biological pathways were studied using GSVA and GSEA. Six algorithms were used to compare immune infiltration between the two risk groups. Furthermore, drug sensitivity was measured using the “pRRophetic” R package. The predictive capacity of the 3-UPSGs signature for sensitivity to immunotherapy was also explored. Moreover, we performed a pan-cancer analysis of the 3-UPSGs signature.
Results
A risk model containing 3 UPSGs (DCAF13, CDC20 and PSMB5) was developed. IHC and qRT-PCR results showed that signature genes were significantly overexpressed in HCC tissues. The high-risk group had a worse prognosis, with a higher clinicopathological grade, higher levels of tumor mutation burden (TMB), elevated levels of immune checkpoint (IC) expression, as well as increased sensitivity to immunotherapy. The two risk groups also differ in their sensitivity to chemotherapeutic drugs. Furthermore, the three UPSGs may play crucial roles in the progression of multiple types of cancers.
Conclusion
We created a 3-UPSGs signature to estimate the prognosis of HCC and to assist in individualized treatment.
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Date availability
This study utilized publicly available datasets for analysis, and the corresponding links to access these datasets have been incorporated within the text.
Abbreviations
- HCC:
-
Hepatocellular carcinoma
- UPSGs:
-
Ubiquitin proteasome-system genes
- IHC:
-
Immunohistochemistry
- TMB:
-
Tumor mutation burden
- UPS:
-
Ubiquitin–proteasome system
- TME:
-
Tumor microenvironment
- CNV:
-
Copy number variation
- ICIs:
-
Immune checkpoint inhibitors
- TPM:
-
Transcripts Per Kilobase of exon model per Million mapped reads
- DEGs:
-
Differentially expressed genes
- K–M:
-
Kaplan–Meier
- CRL4:
-
Cullin-ring ligase 4
- OS:
-
Overall survival
- IC:
-
Immune checkpoint
- ROC:
-
Receiver operating characteristic
- PCA:
-
Principal component analysis
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Acknowledgements
This work was funded by the National Natural Science Foundation of China (Nos. 8216100399), Jiangxi Province Academic and Technical Leaders Training Program for Major Disciplines (Leading Talents Program: 20213BCJ22014), Jiangxi Provincial Health Commission Science and Technology Program Project (202310030) and Jiangxi Province Key Research and Development Program (20203BBG73056), Jiangxi Provincial Health Commission Technology Plan Project (202310030).
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Z-yL: proposed the research idea. Data was gathered, and the manuscript was written by Y-hL. Z-yL, Y-hL, Q-kZ and B-wL: completed the statistical analysis. LX: reviewed the research framework. All the authors approved the final version.
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Liu, Zy., Li, Yh., Zhang, Qk. et al. Development and validation of a ubiquitin–proteasome system gene signature for prognostic prediction and immune microenvironment evaluation in hepatocellular carcinoma. J Cancer Res Clin Oncol 149, 13363–13382 (2023). https://doi.org/10.1007/s00432-023-05189-w
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DOI: https://doi.org/10.1007/s00432-023-05189-w