High ATF4 expression is associated with poor prognosis, amino acid metabolism, and autophagy in gastric cancer
Open accessAbstract
Background The role of activating transcription factor 4 (ATF4) underlying gastric cancer (GC) remains unclear. The purpose of this study was to investigate the expression levels and biological functions of ATF4 in GC. Methods Expression of ATF4 was detected by quantitative PCR (qPCR), Western blotting, and immunohistochemistry. Cox regression was used for survival analysis and the construction of the nomogram. Immunofluorescence was used to identify the intracellular localization of ATF4. Knockdown and overexpression of ATF4 in GC cells followed by wound healing and Transwell assays, EdU and Calcein-AM/propidium iodide (PI) staining, and cell cycle detection were performed to examine its function in vitro. Transmission electron microscopy was performed to assess the autophagy levels upon ATF4 silencing. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and gene set enrichment analysis (GSEA) were used to determine gene enrichment. SPSS 22.0 software, GraphPad Prism 7.0, and R version 3.6.1 were used for statistical analysis. Results ATF4 expression was upregulated in GC cells and tissues compared with corresponding normal tissues. Survival analysis suggested that a high ATF4 expression was strongly associated with worse overall survival (OS) of GC patients (p < 0.001). The nomogram and the receiver operating characteristic (ROC) curves demonstrated that ATF4 was a highly sensitive and specific prognostic marker of GC [C-index = 0.797, area under the ROC curve (AUC) of 3-year OS = 0.855, and AUC of 5-year OS = 0.863]. In addition, ATF4 knockdown inhibited the cell proliferation, migration, invasion, and cell cycle progression of GC cells in vitro, while overexpression of ATF4 exerted the opposite effects. Bioinformatics analysis showed that ATF4 could promote GC progression possibly by regulating asparagine (Asn) metabolism and autophagy pathways. Further experiments indicated that ATF4 expression was significantly positively correlated with ASNS expression. The inhibition of cell clone formation in Asn-deprived conditions was more significant in the shATF4 group. Finally, we found that ATF4 promoted autophagy through regulating the mTORC1 pathway in GC cells. Conclusion These findings suggested that ATF4 can significantly promote GC development and serve as an independent prognostic factor for GC.
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High expression of genes coding for these enzymes and their transcriptional regulators is strongly associated with shortened patient survival in different types of malignancies.
“The high expression of genes coding for all of these enzymes and their transcriptional regulators is strongly associated with a shortened patient survival in different types of malignancies [66,67,68,69,70,71,72,73,74].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [71]
The up-regulation of glycolysis and one-carbon metabolism, and increased expression of corresponding enzymes, are usually observed in various neoplasms and are associated with metastasis, resistance to therapy, and poor prognosis.
“The up-regulation of glycolysis and one-carbon metabolism, and the increased expression of genes coding for corresponding enzymes, are usually observed in various neoplasms and are associated with metastasis, resistance to therapy, and poor prognosis.”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [71]
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- Authors
- Wang, M., Lu, Y., Wang, H., Wu, Y., Xu, X., & Li, Y.
- Affiliations
- First Affiliated Hospital of Anhui Medical University (CN)
- Corresponding author
- Li, Yongxiang
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2021-12-17
- Volume
- 11
- Pages
- 740120-740120
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC8718699
- OpenAlex
- W4200142340
- Cited by
- 36
- References
- 47
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 13 · 2023: 10 · 2022: 4
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- ATF4, gastric cancer, prognostic factors, asparagine metabolism, asparagine synthetase, autophagy, mTORC1 signaling, cell proliferation, cell migration and invasion, overall survival, amino acid metabolism
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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