Exploring Prognosis, Tumor Microenvironment and Tumor Immune Infiltration in Hepatocellular Carcinoma Based on ATF/CREB Transcription Factor Family Gene-Related Model

Abstract

Honghong Shen,1,* Xianhua Gu,2,* Huiyuan Li,1 Mingyue Tang,1 Xinwei Li,1 Yue Zhang,1 Fang Su,1 Zishu Wang1 1Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China; 2Department of Gynecology Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang Su; Zishu Wang, Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui, 233004, People’s Republic of China, Tel [phone], Email [email protected]; [email protected]: 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.Keywords: hepatocellular carcinoma, ATF/CREB transcription factors, immune checkpoints, prognostic model, nomogram

Keywords

• hepatocellular carcinoma
• atf / creb transcription factors
• immune checkpoints
• prognostic model
• nomogram