International journal of surgery (London, England) · 2025
Comprehensive analysis of an ATF/CREB family-based signature with regard to prognosis and immune feature in adrenocortical carcinoma: a cohort study.
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Wu Kan, Jia Yige, Li Yanxin, Liang Jiayu, Liu Shengzhuo, Zhu Yuchun, Liu Xu, Li Xiang, Liu Zhihong
Аннотация
BACKGROUND: The activating transcription factor (ATF)/cAMP response element-binding protein (CREB) family members play important roles in tumorigenesis and immunity across various cancers. However, their prognostic value and functional relevance in adrenocortical carcinoma (ACC) remain unrevealed.
METHODS: Utilizing RNA-sequencing data from The Cancer Genome Atlas (TCGA), we evaluated the expression levels of 21 ATF/CREB genes in ACC. A seven-gene prognostic model was constructed using LASSO and Cox regression analyses, with the TCGA cohort as the training dataset, and further validated in an external Gene Expression Omnibus (GEO, GSE10927) dataset and a West China Hospital (WCH) cohort by ATF4 immunohistochemical data from 78 samples. Kaplan-Meier and multivariable Cox analyses were performed to assess survival associations. siRNA knockdown and CCK-8 assays in SW13 cells evaluated the biological role of ATF4. Additionally, the relationship between the prognostic signature, immune checkpoints, and immune cell populations was examined.
RESULTS: The ATF/CREB family-based signature significantly stratified ACC cases into high- and low-risk groups based on overall survival in the TCGA dataset. Furthermore, the signature remained an independent prognostic factor in multivariate analyses, and its clinical significance was well validated in different clinical subgroups and independent validation cohorts. Notably, functional assays confirmed that ATF4 knockdown suppressed ACC cell proliferation in vitro , supporting its oncogenic role. Additionally, high-risk signature patients exhibited distinct immune cell proportions and immune-suppressive states, including lower levels of CD8 + T cells, immune checkpoints, and major histocompatibility complex gene expression. Enrichment analyses linked the signature to immune regulation, cytokine signaling, and hormone metabolism pathways.
CONCLUSIONS: We established and validated the first ATF/CREB family-based prognostic model in ACC, integrating transcriptomic, pathological, and functional data. This signature provides prognostic insight and highlights potential for immune stratification and therapeutic targeting in ACC. However, the prediction capability of this signature for predicting prognosis and immunotherapy response warrants further validation.
METHODS: Utilizing RNA-sequencing data from The Cancer Genome Atlas (TCGA), we evaluated the expression levels of 21 ATF/CREB genes in ACC. A seven-gene prognostic model was constructed using LASSO and Cox regression analyses, with the TCGA cohort as the training dataset, and further validated in an external Gene Expression Omnibus (GEO, GSE10927) dataset and a West China Hospital (WCH) cohort by ATF4 immunohistochemical data from 78 samples. Kaplan-Meier and multivariable Cox analyses were performed to assess survival associations. siRNA knockdown and CCK-8 assays in SW13 cells evaluated the biological role of ATF4. Additionally, the relationship between the prognostic signature, immune checkpoints, and immune cell populations was examined.
RESULTS: The ATF/CREB family-based signature significantly stratified ACC cases into high- and low-risk groups based on overall survival in the TCGA dataset. Furthermore, the signature remained an independent prognostic factor in multivariate analyses, and its clinical significance was well validated in different clinical subgroups and independent validation cohorts. Notably, functional assays confirmed that ATF4 knockdown suppressed ACC cell proliferation in vitro , supporting its oncogenic role. Additionally, high-risk signature patients exhibited distinct immune cell proportions and immune-suppressive states, including lower levels of CD8 + T cells, immune checkpoints, and major histocompatibility complex gene expression. Enrichment analyses linked the signature to immune regulation, cytokine signaling, and hormone metabolism pathways.
CONCLUSIONS: We established and validated the first ATF/CREB family-based prognostic model in ACC, integrating transcriptomic, pathological, and functional data. This signature provides prognostic insight and highlights potential for immune stratification and therapeutic targeting in ACC. However, the prediction capability of this signature for predicting prognosis and immunotherapy response warrants further validation.