{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:56:07Z","timestamp":1790592967516,"version":"4.1.0"},"reference-count":61,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Over the past three decades, the biology of EIF3E (int6) has emerged as far more complex than originally anticipated. Initially identified as a common integration site of Mouse Mammary Tumor Virus (MMTV) and subsequently recognized as a component of the eukaryotic translation initiation factor 3 (eIF3) complex, EIF3E is now understood as a multifunctional regulator involved in selective mRNA translation, proteostasis, genome stability, cellular stress responses, and tissue homeostasis. Recent studies have further extended this framework by demonstrating that conditional Eif3e deficiency promotes lymphoma susceptibility in mice, providing in vivo evidence linking EIF3E-dependent translational regulation to immune homeostasis and cancer development. This focused review retraces the scientific journey of EIF3E from its discovery as int6 to the progressive definition of its diverse biological functions and context-dependent roles in cancer. Particular attention is given to the historical relationship between int6 (EIF3E) and int7 (RSPO2), whose unexpected reunion in recurrent EIF3E::RSPO2 fusions in human solid tumors provides a unique bridge between classical retroviral insertional mutagenesis and contemporary cancer genomics. While transcriptional activation of RSPO2 through EIF3E regulatory elements represents the established oncogenic mechanism of the fusion, whether disruption of one EIF3E allele exerts additional biological effects remains unknown. Together, these observations highlight EIF3E as a nexus between selective translation, cellular homeostasis, and cancer, while emerging links between epigenomic, epitranscriptomic, and translational regulation open new perspectives for understanding its context-dependent functions in tumorigenesis.<\/jats:p>","DOI":"10.3390\/cancers18193120","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:00:34Z","timestamp":1790589634000},"page":"3120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Complex Biology of EIF3E (int6): From Its Original Discovery to EIF3E::RSPO2 Fusions in Solid Tumors and Lymphoma Susceptibility"],"prefix":"10.3390","volume":"18","author":[{"given":"Antonio","family":"Marchetti","sequence":"first","affiliation":[{"name":"Department of Medical, Oral and Biotechnological Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiamma","family":"Buttitta","sequence":"additional","affiliation":[{"name":"Department of Medical, Oral and Biotechnological Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0092-8674(82)90409-3","article-title":"Many tumors induced by mouse mammary tumor virus contain a provirus integrated in the same region of the host genome","volume":"31","author":"Nusse","year":"1982","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1126\/science.6177038","article-title":"Form and function of retroviral proviruses","volume":"216","author":"Varmus","year":"1982","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/0092-8674(84)90383-0","article-title":"Tumorigenesis by mouse mammary tumor virus: Proviral activation of a cellular gene in the common integration region int2","volume":"37","author":"Dickson","year":"1984","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1128\/jvi.61.1.218-220.1987","article-title":"A new common integration region (int3) for mouse mammary tumor virus on mouse chromosome 17","volume":"61","author":"Gallahan","year":"1987","journal-title":"J. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1038\/sj.onc.1203276","article-title":"MMTV-induced mammary tumorigenesis: Gene discovery, progression to malignancy and cellular pathways","volume":"19","author":"Callahan","year":"2000","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s10911-008-9092-6","article-title":"Common integration sites for MMTV in viral induced mouse mammary tumors","volume":"13","author":"Callahan","year":"2008","journal-title":"J. Mammary Gland Biol. Neoplasia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1128\/jvi.69.3.1932-1938.1995","article-title":"Int-6, a highly conserved, widely expressed gene, is mutated by mouse mammary tumor virus in mammary preneoplasia","volume":"69","author":"Marchetti","year":"1995","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"23477","DOI":"10.1074\/jbc.272.38.23477","article-title":"The Translation Initiation Factor eIF3-p48 Subunit Is Encoded by int-6, a Site of Frequent Integration by the Mouse Mammary Tumor Virus Genome","volume":"272","author":"Asano","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1074\/jbc.272.2.1101","article-title":"Conservation and diversity of eukaryotic translation initiation factor eIF3. Characterization of cDNAs encoding five subunits of human eIF3","volume":"272","author":"Asano","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S0968-0004(01)01825-4","article-title":"Unified nomenclature for the subunits of eukaryotic initiation factor 3","volume":"26","author":"Browning","year":"2001","journal-title":"Trends Biochem. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12707","DOI":"10.1074\/jbc.M700423200","article-title":"Mammalian tumor suppressor Int6 specifically targets hypoxia inducible factor 2 alpha for degradation by hypoxia- and pVHL-independent regulation","volume":"282","author":"Chen","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1158\/0008-5472.CAN-11-2562","article-title":"INT6\/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells","volume":"72","author":"Morris","year":"2012","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6054","DOI":"10.1158\/0008-5472.CAN-16-0723","article-title":"INT6\/EIF3E Controls the RNF8-Dependent Ubiquitylation Pathway and Facilitates DNA Double-Strand Break Repair in Human Cells","volume":"76","author":"Morris","year":"2016","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/nature11282","article-title":"Recurrent R-spondin fusions in colon cancer","volume":"488","author":"Seshagiri","year":"2012","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e20251968","DOI":"10.1084\/jem.20251968","article-title":"eIF3e-mediated translational checkpoint maintains immune tolerance and prevents lymphoid malignancy","volume":"223","author":"Lin","year":"2026","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10056","DOI":"10.1074\/jbc.M010188200","article-title":"Fission yeast homolog of murine Int-6 protein, encoded by mouse mammary tumor virus integration site, is associated with the conserved core subunits of eukaryotic translation initiation factor 3","volume":"276","author":"Akiyoshi","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"45988","DOI":"10.1074\/jbc.M104966200","article-title":"The human protein HSPC021 interacts with Int-6 and is associated with eukaryotic translation initiation factor 3","volume":"276","author":"Ferro","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0092-8674(03)00043-6","article-title":"Schizosaccharomyces pombe Int6 and Ras homologs regulate cell division and mitotic fidelity via the proteasome","volume":"112","author":"Yen","year":"2003","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1074\/jbc.M107790200","article-title":"Moe1 and spInt6, the fission yeast homologues of mammalian translation initiation factor 3 subunits p66 (eIF3d) and p48 (eIF3e), respectively, are required for stable association of eIF3 subunits","volume":"277","author":"Bandyopadhyay","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0014-5793(02)03147-2","article-title":"Association of the mammalian proto-oncoprotein Int-6 with the three protein complexes eIF3, COP9 signalosome and 26S proteasome","volume":"527","author":"Bochard","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0014-5793(98)01367-2","article-title":"The Arabidopsis homologue of an eIF3 complex subunit associates with the COP9 complex","volume":"439","author":"Karniol","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1074\/jbc.M006721200","article-title":"Arabidopsis eIF3e (INT-6) associates with both eIF3c and the COP9 signalosome subunit CSN7","volume":"276","author":"Yahalom","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4005","DOI":"10.1091\/mbc.11.11.4005","article-title":"Fission yeast Int6 is not essential for global translation initiation, but deletion of int6(+) causes hypersensitivity to caffeine and affects spore formation","volume":"11","author":"Bandyopadhyay","year":"2000","journal-title":"Mol. Biol. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"30669","DOI":"10.1074\/jbc.M302093200","article-title":"Rpn5 is a conserved proteasome subunit and required for proper proteasome localization and assembly","volume":"278","author":"Yen","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhou, C., Arslan, F., Wee, S., Krishnan, S., Ivanov, A.R., Oliva, A., Leatherwood, J., and Wolf, D.A. (2005). PCI proteins eIF3e and eIF3m define distinct translation initiation factor 3 complexes. BMC Biol., 3.","DOI":"10.1186\/1741-7007-3-14"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/onc.2010.445","article-title":"Int6 regulates both proteasomal degradation and translation initiation and is critical for proper formation of acini by human mammary epithelium","volume":"30","author":"Suo","year":"2011","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.molcel.2020.06.003","article-title":"eIF3 Associates with 80S Ribosomes to Promote Translation Elongation, Mitochondrial Homeostasis, and Muscle Health","volume":"79","author":"Lin","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"116662","DOI":"10.1016\/j.celrep.2025.116662","article-title":"5\u2019 UTR-mediated retention of eIF3 on 80S ribosomes promotes co-translational folding of ER membrane proteins","volume":"44","author":"Han","year":"2025","journal-title":"Cell Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"R323","DOI":"10.1016\/S0960-9822(03)00238-0","article-title":"Protein homeostasis: A degrading role for Int6\/eIF3e","volume":"13","author":"Chamovitz","year":"2003","journal-title":"Curr. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8235121","DOI":"10.1155\/2016\/8235121","article-title":"Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression","volume":"2016","author":"Sharma","year":"2016","journal-title":"J. Nucleic Acids"},{"key":"ref_31","first-page":"175","article-title":"Reduced expression of INT-6\/eIF3-p48 in human tumors","volume":"18","author":"Marchetti","year":"2001","journal-title":"Int. J. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1158\/1078-0432.CCR-04-2308","article-title":"Int6 expression can predict survival in early-stage non-small cell lung cancer patients","volume":"11","author":"Buttitta","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3598","DOI":"10.1038\/onc.2012.371","article-title":"Decreased eIF3e\/Int6 expression causes epithelial-to-mesenchymal transition in breast epithelial cells","volume":"32","author":"Gillis","year":"2013","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5291","DOI":"10.1038\/sj.onc.1204624","article-title":"Evidence for the transforming activity of a truncated Int6 gene, in vitro","volume":"20","author":"Rasmussen","year":"2001","journal-title":"Oncogene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0014-5793(02)02307-4","article-title":"Malignant transformation by the eukaryotic translation initiation factor 3 subunit p48 (eIF3e)","volume":"514","author":"Mayeur","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"R42","DOI":"10.1186\/bcr1742","article-title":"Expression of truncated Int6\/eIF3e in mammary alveolar epithelium leads to persistent hyperplasia and tumorigenesis","volume":"9","author":"Mack","year":"2007","journal-title":"Breast Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4080","DOI":"10.1038\/onc.2010.152","article-title":"An oncogenic role of eIF3e\/INT6 in human breast cancer","volume":"29","author":"Grzmil","year":"2010","journal-title":"Oncogene"},{"key":"ref_38","first-page":"6462","article-title":"Overexpression of eIF3e is correlated with colon tumor development and poor prognosis","volume":"7","author":"Li","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.7150\/jca.22546","article-title":"Up-regulation of EIF3e Is Associated with The Progression of Esophageal Squamous Cell Carcinoma and Poor Prognosis in Patients","volume":"9","author":"Xu","year":"2018","journal-title":"J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.3390\/ijms15022172","article-title":"Int6\/eIF3e is essential for proliferation and survival of human glioblastoma cells","volume":"15","author":"Sesen","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"zcaa020","DOI":"10.1093\/narcan\/zcaa020","article-title":"Translation reprogramming by eIF3 linked to glioblastoma resistance","volume":"2","author":"Bertorello","year":"2020","journal-title":"NAR Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.cyto.2013.01.021","article-title":"Int6\/eIF3e silenced HIF2\u03b1 stabilization enhances migration and tube formation of HUVECs via IL-6 and IL-8 signaling","volume":"62","author":"Endler","year":"2013","journal-title":"Cytokine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1006\/geno.1997.4996","article-title":"The chromosome location of the human homolog of the mouse mammary tumor-associated gene INT6 and its status in human breast carcinomas","volume":"46","author":"Miyazaki","year":"1997","journal-title":"Genomics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10093","DOI":"10.1128\/JVI.79.15.10093-10096.2005","article-title":"A new common integration site, Int7, for the mouse mammary tumor virus in mouse mammary tumors identifies a gene whose product has furin-like and thrombospondin-like sequences","volume":"79","author":"Lowther","year":"2005","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1038\/s41416-022-01880-w","article-title":"Clinicopathological and molecular characteristics of RSPO fusion-positive colorectal cancer","volume":"127","author":"Hashimoto","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/his.13867","article-title":"EIF3E-RSPO2 and PIEZO1-RSPO2 fusions in colorectal traditional serrated adenoma","volume":"75","author":"Hashimoto","year":"2019","journal-title":"Histopathology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/his.13265","article-title":"Comprehensive characterization of RSPO fusions in colorectal traditional serrated adenomas","volume":"71","author":"Sekine","year":"2017","journal-title":"Histopathology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e23250","DOI":"10.1002\/gcc.23250","article-title":"Identification of rare EIF3E::RSPO2 fusion in recurrent and aggressive urachal adenocarcinoma","volume":"63","author":"Jha","year":"2024","journal-title":"Genes Chromosom. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Sayagu\u00e9s, J.M., Abad, M., Bueno-Sacrist\u00e1n, D., Sancho, M., Rivas, M.B., Alonso-M\u00e1rquez, M.T., Moreno, A.M., and Montero, J.C. (2026). EIF3E::RSPO2 fusion in metastatic pancreatic ductal adenocarcinoma: A clinical case report suggesting a putative KRAS-independent molecular profile. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27135679"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15945","DOI":"10.1038\/ncomms15945","article-title":"R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine","volume":"8","author":"Han","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1002\/2211-5463.12482","article-title":"Eukaryotic translation initiation factor 3 (eIF3) subunit e is essential for embryonic development and cell proliferation","volume":"8","author":"Sadato","year":"2018","journal-title":"FEBS Open Bio"},{"key":"ref_52","first-page":"1","article-title":"The Bad, the Good and eIF3e\/INT6","volume":"22","author":"Sesen","year":"2017","journal-title":"Front Biosci. (Landmark Ed.)"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/nrc3130","article-title":"A decade of exploring the cancer epigenome\u2014Biological and translational implications","volume":"11","author":"Baylin","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1056\/NEJMra1402513","article-title":"The key role of epigenetics in human disease prevention and mitigation","volume":"378","author":"Feinberg","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1002\/ijc.31014","article-title":"Roadmap for investigating epigenome deregulation and environmental origins of cancer","volume":"142","author":"Herceg","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.3324\/haematol.2023.283467","article-title":"Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma","volume":"109","author":"Chong","year":"2024","journal-title":"Haematologica"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e20260912","DOI":"10.1084\/jem.20260912","article-title":"Flawed translation triggers oncogenic B-T cell communication","volume":"223","author":"Supprian","year":"2026","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nature14267","article-title":"eIF3 targets cell-proliferation messenger RNAs for translational activation or repression","volume":"522","author":"Lee","year":"2015","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.cell.2015.10.012","article-title":"5\u2032 UTR m6A promotes cap-independent translation","volume":"163","author":"Meyer","year":"2015","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/s41586-018-0538-8","article-title":"mRNA circularization by METTL3\u2013eIF3h enhances translation and promotes oncogenesis","volume":"561","author":"Choe","year":"2018","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/s41556-021-00835-2","article-title":"METTL16 promotes translation through interaction with the eIF3 complex","volume":"24","author":"Su","year":"2022","journal-title":"Nat. Cell Biol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3120\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:01:59Z","timestamp":1790589719000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,26]]},"references-count":61,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cancers18193120"],"URL":"https:\/\/doi.org\/10.3390\/cancers18193120","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,26]]}}}