Deep computational analysis details dysregulation of eukaryotic translation initiation complex eIF4F in human cancers
Open accessAbstract
eIF4F plays diverse roles in human cancers, which complicate the development of an overarching understanding of its functional and regulatory impacts across tumor types. Typically, eIF4F drives initiation from the mRNA 5' end (cap) and is composed of eIF4G1, eIF4A1, and cap-binding eIF4E. Cap-independent initiation is possible without eIF4E, from internal ribosomal entry sites (IRESs). By analyzing large public datasets, we found that cancers selectively overexpress EIF4G1 more than EIF4E. That expression imbalance supports EIF4G1 as a prognostic indicator in patients with cancer. It also attenuates "housekeeping" pathways that are usually regulated in a tissue-specific manner via cap-dependent initiation in healthy tissues and reinforce regulation of cancer-preferred pathways in cap-independent contexts. Cap-independent initiation is mechanistically attributable to eIF4G1 hyperphosphorylation that promotes binding to eIF4A1 and reduced eIF4E availability. Collectively, these findings reveal a novel model of dysregulated eIF4F function and highlight the clinical relevance of cap-(in)dependent initiation in cancer.
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Elevated EIF4G1 mRNA levels correlate with poor survival in patients with MFS and those with UPS.
“Elevated EIF4G1 mRNA levels correlate with poor survival in patients with MFS and those with UPS, consistent with findings from a previous study (41).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [41]
The Results section, “EIF4G1 Expression Is a Strong Predictor for Survival in Patients with Cancer” (page unavailable), links high EIF4G1 expression to worse survival across TCGA cancer types combined and separately in lung adenocarcinoma. It does not report this association specifically for patients with MFS or UPS, so it supports the general finding but not the claimed populations. (LLM, conf=0.88)
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Levy, T., Voeltzke, K., Hruby, L. A., Alasad, K., Bas, Z., Snaebjornsson, M. T., Marciano, R., Scharov, K., Planque, M., Vriens, K., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48386-y · Cited by 53 · see citing works
EIF4G1 Is a Potential Prognostic Biomarker of Breast Cancer
Li, K., Tan, G., Zhang, X., Lu, W., Ren, J., Si, Y., Adu‐Gyamfi, E. A., Li, F., Wang, Y., Xie, B., et al. (2022) · Biomolecules · doi:10.3390/biom12121756 · Cited by 23 · see citing works
Montero‐Hidalgo, A. J., Jiménez‐Vacas, J. M., Gómez‐Gómez, E., Porcel-Pastrana, F., Sáez-Martínez, P., Pérez‐Gómez, J. M., Fuentes-Fayos, A. C., Blázquez‐Encinas, R., Sánchez‐Sánchez, R., González-Serrano, T., et al. (2024) · Science Advances · doi:10.1126/sciadv.ado8231 · Cited by 17 · see citing works
Therapeutic targeting of eukaryotic initiation factor (eIF) 4E
Pelletier, J., & Sonenberg, N. (2023) · Biochemical Society Transactions · doi:10.1042/bst20220285 · Cited by 11 · see citing works
He, C., Zhang, X.-D., Zhu, S., Zheng, J., Wang, Y., Wang, Q., Yin, H., Fu, Y.-J., Song, X., Tang, J., et al. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.998147 · Cited by 11 · see citing works
Li, Z., Wang, W., Wu, J., & Ye, X. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.962972 · Cited by 9 · see citing works
Computational inference of eIF4F complex function and structure in human cancers
Wu, S., & Wagner, G. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2313589121 · Cited by 7 · see citing works
Self-citationBanerjee, S., Chandu, P. M., Sarkar, M., Soni, T. K., Saha, M., Fathah Muhammad, L., Chatterjee, B., & Das, U. (2025) · Neurological Research · doi:10.1080/01616412.2025.2600434 · Cited by 4 · see citing works
Hruby, L., Schaal, K., Delaidelli, A., Picard, D. J., Dunham, C. P., Lewandowska, O., Reiff, T., Larcher, M., Pouponnot, C., Sorensen, P. H. B., et al. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02601-x · Cited by 3 · see citing works
Wu, S., & Wagner, G. (2022) · STAR Protocols · doi:10.1016/j.xpro.2022.101880 · Cited by 2 · see citing works
Self-citationLevy, T., Voeltzke, K., Hauffe, L., Alasad, K., Snaebjörnsson, M., Marciano, R., Scharov, K., Planque, M., Vriens, K., Christen, S., et al. (2022) · bioRxiv · doi:10.1101/2022.09.09.507243 · Cited by 1 · see citing works
Klapp, V., Gumustekin, O., Paggetti, J., Moussay, E., & Largeot, A. (2024) · Methods in cell biology · doi:10.1016/bs.mcb.2024.06.006 · Cited by 1 · see citing works
Chin, V. T., Muskovic, W., McCloy, R. A., Neavin, D. R., Alquicira-Hernández, J., Arora, H., Senabouth, A., Sudhakar, K. K., Keith, P., Spenceley, E., et al. (2025) · BMC Medicine · doi:10.1186/s12916-025-04392-5 · Cited by 1 · see citing works
Smith, R. J., Diba, L. Z., Srinivasan, A., Zollo, R. A., Ossevoort, T., He, Q., Colligan, S. H., Dolan, M., Vedire, Y., Sultana, T., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.16.508318 · Cited by 1 · see citing works
Hruby, L., Scharov, K., Delaidelli, A., Picard, D. J., Dunham, C. P., Lewandowska, O., Reiff, T., Larcher, M., Pouponnot, C., Sorensen, P. H. B., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.06.583558 · Cited by 1 · see citing works
Targeting eIF4A-dependent translation in genetically complex sarcoma
Kim, Y.-M., Mohan, P., Sehrawat, U., Seffar, E., De Queiroz, R. M., Chadalavada, K., Persaud, N., Okada, T., Kulkarni, A., Lin, J., et al. (2026) · JCI Insight · doi:10.1172/jci.insight.192936
Chin, V. T., Muskovic, W., McCloy, R. A., Neavin, D. R., Alquicira-Hernández, J., Arora, H., Senabouth, A., Keith, P., Spenceley, E., Murphy, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.15.589624
Dreno, L., Ousalem, F., Albornoz-Loaiza, A., CELIK, B., Tiraboschi, C., Claps, G., Al-Nakouzi, N., Compagno, D., Dayris, T., Aglave, M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.18.700172
Duan, J., Zhang, H., Chu, J., & Duan, X. (2026) · Experimental Hematology · doi:10.1016/j.exphem.2026.105870
Yen, R., Wu, A., Chen, M., Yue, L., Lizardo, M. M., Hughes, C. S., Leung, J., Liu, Y., Forrest, D. L., Sorensen, P. H. B., et al. (2026) · Leukemia · doi:10.1038/s41375-026-03157-0
- Authors
- Wu, S., & Wagner, G.
- Affiliations
- Harvard University (US)
- Corresponding author
- Wu, Su
- Wagner, Gerhard
- Venue
- Cell Systems
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 12
- Issue
- 9
- Pages
- 907-923.e6
- ISSN
- 2405-4712 (ISSN-L)
- PMC
- PMC8460614
- OpenAlex
- W3190569063
- Cited by
- 20
- References
- 90
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 7 · 2023: 1 · 2022: 6
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 386 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Systems (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (5R01AI037581-25, 5R01CA200913-05)
- NIGMS
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- eIF4F, translation initiation, eIF4G1, eIF4E, eIF4A1, internal ribosome entry site, protein phosphorylation, cancer, prognostic factors, mRNA 5' cap, tumor-specific gene expression
- MeSH terms
- Humans, Neoplasms, Protein Biosynthesis, Eukaryotic Initiation Factor-4F, Eukaryotic Initiation Factor-4G, Eukaryota
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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