https://orcid.org/0000-0002-8412-331X
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Abstract
Introduction
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. It is the fourth leading cause of cancer-related death worldwide. Deregulation of the ATF/CREB family is associated with the progression of metabolic homeostasis and cancer. Because the liver plays a central role in metabolic homeostasis, it is critical to assess the predictive value of the ATF/CREB family in the diagnosis and prognosis of HCC.
Methods
Using data from The Cancer Genome Atlas (TCGA), this research evaluated the expression, copy number variations, and frequency of somatic mutations of 21 genes in the ATF/CREB family in HCC. A prognostic model based on the ATF/CREB gene family was developed via Lasso and Cox regression analyses, with the TCGA cohort serving as the training dataset and the International Cancer Genome Consortium (ICGC) cohort serving as the validation set. Kaplan-Meier and receiver operating characteristic analyses verified the accuracy of the prognostic model. Furthermore, the association among the prognostic model, immune checkpoints, and immune cells was examined.
Results
High-risk patients exhibited an unfavorable outcome as opposed to those in the low-risk category. Multivariate Cox analysis revealed that the risk score calculated based on the prognostic model was an independent prognostic factor for HCC. Analysis of immune mechanisms revealed that the risk score had a positive link to the expression of immune checkpoints, particularly CD274, PDCD1, LAG3, and CTLA4. Differences in immune cells and immune-associated roles were found between the high- and low-risk patients, as determined by single-sample gene set enrichment analysis. The core genes ATF1, CREB1, and CREB3 in the prognostic model were shown to be upregulated in HCC tissues as opposed to adjoining normal tissues, and the 10-year overall survival (OS) rate was worse among patients with elevated expression levels of ATF1, CREB1, and CREB3. Elevated expression levels of ATF1, CREB1, and CREB3 in HCC tissues were confirmed by qRT-PCR and immunohistochemistry studies.
Conclusion
According to the results of our training set and test set, the risk model based on the six ATF/CREB gene signatures predicting prognosis has certain predictive accuracy in predicting the survival of HCC patients. This study provides novel insights into the individualized treatment of patients with HCC.
Abbreviations
HCC, hepatocellular carcinoma; TCGA, The Cancer Genome Atlas; ICGC, the International Cancer Genome Consortium; OS, overall survival; CNVs, copy number variations; C-index, concordance index; GSEA, Gene set enrichment analysis; IHC, Immunohistochemistry; RT, room temperature; qRT-PCR, Quantitative reverse transcription polymerase chain reaction; DCs, resting dendritic cells; KM, Kaplan-Meier; FDR, false discovery rate; AUC, area under the curve; ROC, Receiver operating characteristic.
Data Sharing Statement
This study analysed used clinical data publicly available in the following online databases: TCGA (https://www.cancer.gov/), ICGC (https://dcc.icgc.org), and CellMiner (https://discover.nci.nih.gov/cellminer/home.do).
Ethics Approval and Informed Consent
Human subject research was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Bengbu Medical College [2022] 298. The study was performed in compliance with the Helsinki Declaration. All original liver donations were conducted voluntarily, with written informed consent and in compliance with the Declaration of Istanbul.
Acknowledgments
We thank Bullet Edits Limited for language editing and proofreading of the manuscript and open databases such as TCGA, ICGC, and CellMiner for providing the platform and datasets.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.