{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:01:37Z","timestamp":1787580097362,"version":"build-2736575974"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:00:00Z","timestamp":1710892800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:00:00Z","timestamp":1710892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007128","name":"the Natural Science Foundation of Shaanxi Province","doi-asserted-by":"crossref","award":["2020JQ-539"],"award-info":[{"award-number":["2020JQ-539"]}],"id":[{"id":"10.13039\/501100007128","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cancer Res Clin Oncol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Acute myeloid leukemia (AML) is a hematological malignancy derived from the accumulation of abnormal proliferation of infantile leukocytes in the hematopoietic system. DNA-damage-inducible transcript 4 (<jats:italic>DDIT4<\/jats:italic>) acting as a negative regulator of rapamycin inhibitor is involved in various cellular functions. Many studies have suggested that <jats:italic>DDIT4<\/jats:italic> plays a key role in tumorigenesis. However, the role of <jats:italic>DDIT4<\/jats:italic> in AML has been poorly studied.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Method<\/jats:title>\n                <jats:p>In this study, we analyzed the expression of <jats:italic>DDIT4<\/jats:italic> in AML patients using The Cancer Genome Atlas and real-time polymerase chain reaction. The Chi-square test was used to assess the correlation between <jats:italic>DDIT4<\/jats:italic> and clinical characters in AML patients. Loss-of-function experiments were implemented to investigate the role of <jats:italic>DDIT4<\/jats:italic> in AML carcinogenesis. The R package was applied to evaluate the correlation between <jats:italic>DDIT4<\/jats:italic> expression and immune cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Results showed that the expression of <jats:italic>DDIT4<\/jats:italic> was associated with Age, Cytogenetic risk, Cytogenetics and OS event. Moreover, high expression of <jats:italic>DDIT4<\/jats:italic> led to a terrible prognosis. KEGG analysis showed that differently expressed genes (DEGs) were involved in the PI3-Akt signaling pathway. GSEA enrichment analysis displayed DEGs were correlated with apoptosis. Functional experiments presented that knocking down <jats:italic>DDIT4<\/jats:italic> suppressed cell cycle transition\/proliferation and facilitated apoptosis. In addition, <jats:italic>DDIT4<\/jats:italic> is associated with immune infiltration.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our research verified that <jats:italic>DDIT4<\/jats:italic> can be used as a prognostic marker and a potential therapeutic target for AML.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00432-024-05676-8","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T05:54:28Z","timestamp":1710914068000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pan-cancer analysis of DDIT4 identifying its prognostic value and function in acute myeloid leukemia"],"prefix":"10.1007","volume":"150","author":[{"given":"Fangmei","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyu","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aili","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,20]]},"reference":[{"key":"5676_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2019.100645","volume":"46","author":"YG Assaraf","year":"2019","unstructured":"Assaraf YG, Brozovic A, Gon\u00e7alves AC, Jurkovicova D, Lin\u0113 A, Machuqueiro M, Saponara S, Sarmento-Ribeiro AB, Xavier CPR, Vasconcelos MH (2019) The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist Updat 46:100645","journal-title":"Drug Resist Updat"},{"key":"5676_CR2","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/j.immuni.2013.10.003","volume":"39","author":"G Bindea","year":"2013","unstructured":"Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, Bruneval P, Fridman WH, Becker C, Pag\u00e8s F, Speicher MR, Trajanoski Z, Galon J (2013) Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39:782\u2013795","journal-title":"Immunity"},{"key":"5676_CR3","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1111\/jcmm.14831","volume":"24","author":"Z Cheng","year":"2020","unstructured":"Cheng Z, Dai Y, Pang Y, Jiao Y, Liu Y, Cui L, Quan L, Qian T, Zeng T, Si C, Huang W, Chen J, Pang Y, Ye X, Shi J, Fu L (2020) Up-regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia. J Cell Mol Med 24:1067\u20131075","journal-title":"J Cell Mol Med"},{"key":"5676_CR4","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/nmeth.1607","volume":"8","author":"K Colwill","year":"2011","unstructured":"Colwill K, Gr\u00e4slund S (2011) A roadmap to generate renewable protein binders to the human proteome. Nat Methods 8:551\u2013558","journal-title":"Nat Methods"},{"key":"5676_CR5","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1056\/NEJMra1406184","volume":"373","author":"H D\u00f6hner","year":"2015","unstructured":"D\u00f6hner H, Weisdorf DJ, Bloomfield CD (2015) Acute myeloid Leukemia. N Engl J Med 373:1136\u20131152","journal-title":"N Engl J Med"},{"key":"5676_CR6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0125728","volume":"10","author":"JM Gwak","year":"2015","unstructured":"Gwak JM, Jang MH, Kim DI, Seo AN, Park SY (2015) Prognostic value of tumor-associated macrophages according to histologic locations and hormone receptor status in breast cancer. PLoS ONE 10:e0125728","journal-title":"PLoS ONE"},{"key":"5676_CR7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","volume":"14","author":"S H\u00e4nzelmann","year":"2013","unstructured":"H\u00e4nzelmann S, Castelo R, Guinney J (2013) GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14:7","journal-title":"BMC Bioinformatics"},{"key":"5676_CR8","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1126\/science.aal3535","volume":"356","author":"WE Ip","year":"2017","unstructured":"Ip WE, Hoshi N, Shouval DS, Snapper S, Medzhitov R (2017) Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356:513\u2013519","journal-title":"Science"},{"key":"5676_CR9","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1016\/j.clml.2021.05.016","volume":"21","author":"HM Kantarjian","year":"2021","unstructured":"Kantarjian HM, Short NJ, Fathi AT, Marcucci G, Ravandi F, Tallman M, Wang ES, Wei AH (2021) Acute myeloid leukemia: historical perspective and progress in research and therapy over 5 decades. Clin Lymphoma Myeloma Leuk 21:580\u2013597","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"5676_CR10","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","volume":"368","author":"TJ Ley","year":"2013","unstructured":"Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, Mclellan MD, Mcmichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, Wartman LD, Watson MA, Welch J, Wendl MC, Ally A, Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez C, Zou L, Leiserson MD, Vandin F, Wu HT, Applebaum F, Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KR, Sheth M, Sofia HJ, Yang L, Downing JR, Eley G (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368:2059\u201374","journal-title":"N Engl J Med"},{"key":"5676_CR11","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1080\/15384101.2019.1578146","volume":"18","author":"C Liu","year":"2019","unstructured":"Liu C, Li Y, Wei M, Zhao L, Yu Y, Li G (2019) Identification of a novel glycolysis-related gene signature that can predict the survival of patients with lung adenocarcinoma. Cell Cycle 18:568\u2013579","journal-title":"Cell Cycle"},{"key":"5676_CR12","unstructured":"National Cancer Institute. Cancer stat facts: leukemia\u2014acute myeloid leukemia (AML).https:\/\/seer.cancer.gov\/statfacts\/html\/amyl.html. https:\/\/seer.cancer.gov\/statfacts\/html\/amyl.html. 2021. Cancer Stat Facts: Leukemia\u2014Acute Myeloid Leukemia (AML). https:\/\/seer.cancer.gov\/statfacts\/html\/amyl.htmlhttps:\/\/seer.cancer.gov\/statfacts\/html\/amyl.html. Accessed 21 Sep 2017."},{"key":"5676_CR13","doi-asserted-by":"publisher","first-page":"9139","DOI":"10.1038\/s41598-019-45579-0","volume":"9","author":"CH Nguyen","year":"2019","unstructured":"Nguyen CH, Gl\u00fcxam T, Schlerka A, Bauer K, Grandits AM, Hackl H, Dovey O, Z\u00f6chbauer-M\u00fcller S, Cooper JL, Vassiliou GS, Stoiber D, Wieser R, Heller G (2019) SOCS2 is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness. Sci Rep 9:9139","journal-title":"Sci Rep"},{"key":"5676_CR14","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1016\/j.cellsig.2016.04.004","volume":"28","author":"J Pinno","year":"2016","unstructured":"Pinno J, Bongartz H, Klepsch O, Wundrack N, Poli V, Schaper F, Dittrich A (2016) Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner. Cell Signal 28:907\u2013916","journal-title":"Cell Signal"},{"key":"5676_CR15","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1038\/s41598-017-01207-3","volume":"7","author":"JA Pinto","year":"2017","unstructured":"Pinto JA, Rolfo C, Raez LE, Prado A, Araujo JM, Bravo L, Fajardo W, Morante ZD, Aguilar A, Neciosup SP, Mas LA, Bretel D, Balko JM, Gomez HL (2017) In silico evaluation of DNA damage inducible transcript 4 gene (DDIT4) as prognostic biomarker in several malignancies. Sci Rep 7:1526","journal-title":"Sci Rep"},{"key":"5676_CR16","doi-asserted-by":"publisher","first-page":"64","DOI":"10.3389\/fonc.2014.00064","volume":"4","author":"C Porta","year":"2014","unstructured":"Porta C, Paglino C, Mosca A (2014) Targeting PI3K\/Akt\/mTOR Signaling in cancer. Front Oncol 4:64","journal-title":"Front Oncol"},{"key":"5676_CR17","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.619085","volume":"10","author":"PK Reville","year":"2020","unstructured":"Reville PK, Kadia TM (2020) Maintenance therapy in AML. Front Oncol 10:619085","journal-title":"Front Oncol"},{"key":"5676_CR18","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498\u20132504","journal-title":"Genome Res"},{"key":"5676_CR19","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1002\/ajh.26822","volume":"98","author":"S Shimony","year":"2023","unstructured":"Shimony S, Stahl M, Stone RM (2023) Acute myeloid leukemia: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol 98:502\u2013526","journal-title":"Am J Hematol"},{"key":"5676_CR20","doi-asserted-by":"publisher","first-page":"2283","DOI":"10.1128\/MCB.22.7.2283-2293.2002","volume":"22","author":"T Shoshani","year":"2002","unstructured":"Shoshani T, Faerman A, Mett I, Zelin E, Tenne T, Gorodin S, Moshel Y, Elbaz S, Budanov A, Chajut A, Kalinski H, Kamer I, Rozen A, Mor O, Keshet E, Leshkowitz D, Einat P, Skaliter R, Feinstein E (2002) Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Mol Cell Biol 22:2283\u20132293","journal-title":"Mol Cell Biol"},{"key":"5676_CR21","doi-asserted-by":"publisher","first-page":"14543","DOI":"10.3390\/ijms232314543","volume":"23","author":"S Small","year":"2022","unstructured":"Small S, Oh TS, Platanias LC (2022) Role of biomarkers in the management of acute myeloid leukemia. Int J Mol Sci 23:14543","journal-title":"Int J Mol Sci"},{"key":"5676_CR22","doi-asserted-by":"publisher","first-page":"5834","DOI":"10.1128\/MCB.25.14.5834-5845.2005","volume":"25","author":"A Sofer","year":"2005","unstructured":"Sofer A, Lei K, Johannessen CM, Ellisen LW (2005) Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol 25:5834\u20135845","journal-title":"Mol Cell Biol"},{"key":"5676_CR23","doi-asserted-by":"publisher","first-page":"3225","DOI":"10.3390\/cancers12113225","volume":"12","author":"M Stanchina","year":"2020","unstructured":"Stanchina M, Soong D, Zheng-Lin B, Watts JM, Taylor J (2020) Advances in acute myeloid leukemia: recently approved therapies and drugs in development. Cancers 12:3225","journal-title":"Cancers"},{"key":"5676_CR24","doi-asserted-by":"publisher","first-page":"5084","DOI":"10.1182\/blood-2011-07-365817","volume":"118","author":"C Ustun","year":"2011","unstructured":"Ustun C, Miller JS, Munn DH, Weisdorf DJ, Blazar BR (2011) Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation? Blood 118:5084\u20135095","journal-title":"Blood"},{"key":"5676_CR25","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1038\/nbt.3772","volume":"35","author":"J Vivian","year":"2017","unstructured":"Vivian J, Rao AA, Nothaft FA, Ketchum C, Armstrong J, Novak A, Pfeil J, Narkizian J, Deran AD, Musselman-Brown A, Schmidt H, Amstutz P, Craft B, Goldman M, Rosenbloom K, Cline M, O\u2019connor B, Hanna M, Birger C, Kent WJ, Patterson DA, Joseph AD, Zhu J, Zaranek S, Getz G, Haussler D, Paten B (2017) Toil enables reproducible, open source, big biomedical data analyses. Nat Biotechnol 35:314\u2013316","journal-title":"Nat Biotechnol"},{"key":"5676_CR26","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.3389\/fimmu.2018.01274","volume":"9","author":"M Wang","year":"2018","unstructured":"Wang M, Zhang C, Tian T, Zhang T, Wang R, Han F, Zhong C, Hua M, Ma D (2018) Increased regulatory T cells in peripheral blood of acute myeloid leukemia patients rely on tumor necrosis factor (TNF)-\u03b1-TNF receptor-2 pathway. Front Immunol 9:1274","journal-title":"Front Immunol"},{"key":"5676_CR27","first-page":"1495","volume":"42","author":"X Zhao","year":"2018","unstructured":"Zhao X, Li Y, Wu H (2018) A novel scoring system for acute myeloid leukemia risk assessment based on the expression levels of six genes. Int J Mol Med 42:1495\u20131507","journal-title":"Int J Mol Med"}],"container-title":["Journal of Cancer Research and Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-024-05676-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00432-024-05676-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-024-05676-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,13]],"date-time":"2024-04-13T11:08:03Z","timestamp":1713006483000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00432-024-05676-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,20]]},"references-count":27,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["5676"],"URL":"https:\/\/doi.org\/10.1007\/s00432-024-05676-8","relation":{},"ISSN":["1432-1335"],"issn-type":[{"value":"1432-1335","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,20]]},"assertion":[{"value":"2 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The authors declare that they have no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"144"}}