{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:37:52Z","timestamp":1791819472259,"version":"4.3.4"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82203734"],"award-info":[{"award-number":["82203734"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Natural Science Foundation of Heilongjiang","award":["YQ2023H006"],"award-info":[{"award-number":["YQ2023H006"]}]},{"name":"Fundamental Research Funds for the Provincial Universities","award":["JFJQPY202401"],"award-info":[{"award-number":["JFJQPY202401"]}]},{"name":"Research Training program (SRT) of Jiaxing University","award":["8517241030"],"award-info":[{"award-number":["8517241030"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited treatment options and poor prognosis. Identifying novel molecular regulators is essential for improving therapeutic strategies. In this study, we identified Sortilin-related VPS10 domain-containing receptor 3 (SorCS3) as a novel tumor suppressor candidate in ACC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Through expression detection and functional validation, we investigated the role of SorCS3, a member of the VPS10p-domain receptor family, in ACC. Expression data from TCGA and clinical tissue samples were analyzed. Endocytic activity, protein interactions, and downstream signaling were examined using immunofluorescence, co-immunoprecipitation (Co-IP), and western blotting in ACC cell lines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SorCS3, previously regarded as CNS-specific, was detected in ACC tissues and cell lines. Low SorCS3 expression was associated with reduced overall survival (OS) and disease-specific survival (DSS). Functional assays showed that SorCS3 enhanced endocytosis and colocalized with early endosomes. Co-IP revealed a physical or indirect interaction between SorCS3 and Insulin-like growth factor 2 receptor (IGF2R), a multifunctional receptor involved in IGF-II degradation and signal attenuation. SorCS3 overexpression (OE-SorCS3) increased IGF2R protein levels and suppressed PI3K\/Akt and MAPK\/Erk signaling. Blocking endocytosis partially reversed these effects, supporting a receptor trafficking-dependent mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In this study, we identified SorCS3 as a novel tumor suppressor candidate in ACC. Although previously thought to be CNS specific, SorCS3 was found to be expressed in ACC tissues and cell lines. Low SorCS3 levels correlated with poor patient survival in the TCGA cohort. Functionally, SorCS3 enhanced endocytosis in ACC cells and physically or indirectly interacted with IGF2R. OE-SorCS3 increased IGF2R protein levels and reduced phosphorylation of Akt\/Erk, suggesting tumor-suppressive effects through IGF2R stabilization and signaling inhibition. Overall, our findings highlight the SorCS3-IGF2R axis as a previously unrecognized regulatory mechanism in ACC progression and suggest that receptor trafficking could be a viable therapeutic target in this malignancy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-025-07146-2","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T10:37:12Z","timestamp":1761043032000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SorCS3 suppresses adrenocortical carcinoma progression by enhancing IGF2R-mediated endocytic trafficking and signaling attenuation"],"prefix":"10.1186","volume":"23","author":[{"given":"Yanqiu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihui","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingqi","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengmiao","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlai","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shipeng","family":"Bo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2026-0769","authenticated-orcid":false,"given":"Dongliang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"issue":"6","key":"7146_CR1","doi-asserted-by":"publisher","first-page":"2027","DOI":"10.1210\/jc.2005-2639","volume":"91","author":"B Allolio","year":"2006","unstructured":"Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab. 2006;91(6):2027\u201337.","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"7146_CR2","doi-asserted-by":"publisher","first-page":"462","DOI":"10.5152\/tud.2017.81598","volume":"43","author":"P Sisman","year":"2017","unstructured":"Sisman P, Sahin AB, Peynirci H, Cander S, Gul OO, Erturk E, et al. Adrenocortical carcinoma: single center experience. Turk J Urol. 2017;43(4):462\u20139.","journal-title":"Turk J Urol"},{"issue":"16","key":"7146_CR3","doi-asserted-by":"publisher","first-page":"2677","DOI":"10.1007\/s00018-009-0043-1","volume":"66","author":"G Hermey","year":"2009","unstructured":"Hermey G. The vps10p-domain receptor family. Cell Mol Life Sci. 2009;66(16):2677\u201389.","journal-title":"Cell Mol Life Sci"},{"issue":"1","key":"7146_CR4","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s13024-022-00576-2","volume":"17","author":"A Salasova","year":"2022","unstructured":"Salasova A, Monti G, Andersen OM, Nykjaer A. Finding memo: versatile interactions of the VPS10p-domain receptors in Alzheimer\u2019s disease. Mol Neurodegener. 2022;17(1):74.","journal-title":"Mol Neurodegener"},{"issue":"41","key":"7146_CR5","doi-asserted-by":"publisher","first-page":"14080","DOI":"10.1523\/JNEUROSCI.3359-12.2012","volume":"32","author":"RF Lane","year":"2012","unstructured":"Lane RF, St George-Hyslop P, Hempstead BL, Small SA, Strittmatter SM, Gandy S. Vps10 family proteins and the retromer complex in aging-related neurodegeneration and diabetes. J Neurosci. 2012;32(41):14080\u20136.","journal-title":"J Neurosci"},{"issue":"9","key":"7146_CR6","doi-asserted-by":"publisher","first-page":"e75006","DOI":"10.1371\/journal.pone.0075006","volume":"8","author":"T Breiderhoff","year":"2013","unstructured":"Breiderhoff T, Christiansen GB, Pallesen LT, Vaegter C, Nykjaer A, Holm MM, et al. Sortilin-related receptor SORCS3 is a postsynaptic modulator of synaptic depression and fear extinction. PLoS ONE. 2013;8(9):e75006.","journal-title":"PLoS ONE"},{"issue":"15","key":"7146_CR7","doi-asserted-by":"publisher","first-page":"3386","DOI":"10.1002\/cne.23606","volume":"522","author":"S Oetjen","year":"2014","unstructured":"Oetjen S, Mahlke C, Hermans-Borgmeyer I, Hermey G. Spatiotemporal expression analysis of the growth factor receptor SorCS3. J Comp Neurol. 2014;522(15):3386\u2013402.","journal-title":"J Comp Neurol"},{"key":"7146_CR8","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201744810","author":"A Subkhangulova","year":"2018","unstructured":"Subkhangulova A, Malik AR, Hermey G, Popp O, Dittmar G, Rathjen T, et al. SORCS1 and SORCS3 control energy balance and orexigenic peptide production. EMBO Rep. 2018. https:\/\/doi.org\/10.15252\/embr.201744810.","journal-title":"EMBO Rep"},{"issue":"5","key":"7146_CR9","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1016\/j.febslet.2004.12.088","volume":"579","author":"UB Westergaard","year":"2005","unstructured":"Westergaard UB, Kirkegaard K, Sorensen ES, Jacobsen C, Nielsen MS, Petersen CM, et al. SorCS3 does not require propeptide cleavage to bind nerve growth factor. FEBS Lett. 2005;579(5):1172\u20136.","journal-title":"FEBS Lett"},{"issue":"4","key":"7146_CR10","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41419-022-04753-5","volume":"13","author":"Y Zhang","year":"2022","unstructured":"Zhang Y, Li Y, Fan Y, Zhang X, Tang Z, Qi J, et al. SorCS3 promotes the internalization of p75(NTR) to inhibit GBM progression. Cell Death Dis. 2022;13(4):313.","journal-title":"Cell Death Dis"},{"issue":"4","key":"7146_CR11","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1007\/s13402-024-00932-y","volume":"47","author":"J Elizazu","year":"2024","unstructured":"Elizazu J, Artetxe-Zurutuza A, Otaegi-Ugartemendia M, Moncho-Amor V, Moreno-Valladares M, Matheu A, et al. Identification of a novel gene signature related to prognosis and metastasis in gastric cancer. Cell Oncol (Dordr). 2024;47(4):1355\u201373.","journal-title":"Cell Oncol (Dordr)"},{"issue":"4","key":"7146_CR12","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1038\/ng1295-447","volume":"11","author":"AT De Souza","year":"1995","unstructured":"De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL. M6P\/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat Genet. 1995;11(4):447\u20139.","journal-title":"Nat Genet"},{"issue":"1","key":"7146_CR13","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1186\/s12967-022-03324-8","volume":"20","author":"D Ma","year":"2022","unstructured":"Ma D, Zhang Q, Duan Q, Tan Y, Sun T, Qi C, et al. Identification of IGF1R mutation as a novel predictor of efficacious immunotherapy in melanoma. J Transl Med. 2022;20(1):172.","journal-title":"J Transl Med"},{"issue":"1","key":"7146_CR14","doi-asserted-by":"publisher","first-page":"309","DOI":"10.3233\/JAD-220574","volume":"89","author":"W Luo","year":"2022","unstructured":"Luo W, Pryzbyl KJ, Bigio EH, Weintraub S, Mesulam MM, Redei EE. Reduced hippocampal and anterior cingulate expression of antioxidant enzymes and membrane progesterone receptors in Alzheimer\u2019s disease with depression. J Alzheimers Dis. 2022;89(1):309\u201321.","journal-title":"J Alzheimers Dis"},{"issue":"3","key":"7146_CR15","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1007\/s12020-019-01869-1","volume":"64","author":"MC De Martino","year":"2019","unstructured":"De Martino MC, van Koetsveld PM, Feelders RA, de Herder WW, Dogan F, Janssen JA, et al. IGF and mTOR pathway expression and in vitro effects of linsitinib and mTOR inhibitors in adrenocortical cancer. Endocrine. 2019;64(3):673\u201384.","journal-title":"Endocrine"},{"issue":"6111","key":"7146_CR16","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1126\/science.1228633","volume":"338","author":"C Williams","year":"2012","unstructured":"Williams C, Hoppe HJ, Rezgui D, Strickland M, Forbes BE, Grutzner F, et al. An exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution. Science. 2012;338(6111):1209\u201313.","journal-title":"Science"},{"issue":"1","key":"7146_CR17","doi-asserted-by":"publisher","first-page":"129","DOI":"10.4149\/neo_2019_190206N108","volume":"67","author":"SB Liu","year":"2020","unstructured":"Liu SB, Zhou LB, Wang HF, Li G, Xie QP, Hu B. Loss of IGF2R indicates a poor prognosis and promotes cell proliferation and tumorigenesis in bladder cancer via AKT signaling pathway. Neoplasma. 2020;67(1):129\u201336.","journal-title":"Neoplasma"},{"issue":"29","key":"7146_CR18","doi-asserted-by":"publisher","first-page":"47269","DOI":"10.18632\/oncotarget.17617","volume":"8","author":"T Li","year":"2017","unstructured":"Li T, Wang J, Liu P, Chi J, Yan H, Lei L, et al. Insulin-like growth factor 2 axis supports the serum-independent growth of malignant rhabdoid tumor and is activated by microenvironment stress. Oncotarget. 2017;8(29):47269\u201383.","journal-title":"Oncotarget"},{"issue":"23","key":"7146_CR19","doi-asserted-by":"publisher","first-page":"13687","DOI":"10.1073\/pnas.95.23.13687","volume":"95","author":"JX Kang","year":"1998","unstructured":"Kang JX, Bell J, Leaf A, Beard RL, Chandraratna RA. Retinoic acid alters the intracellular trafficking of the mannose-6-phosphate\/insulin-like growth factor II receptor and lysosomal enzymes. Proc Natl Acad Sci U S A. 1998;95(23):13687\u201391.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"7146_CR20","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1091\/mbc.e08-06-0569","volume":"20","author":"HB Schiller","year":"2009","unstructured":"Schiller HB, Szekeres A, Binder BR, Stockinger H, Leksa V. Mannose 6-phosphate\/insulin-like growth factor 2 receptor limits cell invasion by controlling alphaVbeta3 integrin expression and proteolytic processing of urokinase-type plasminogen activator receptor. Mol Biol Cell. 2009;20(3):745\u201356.","journal-title":"Mol Biol Cell"},{"issue":"8051","key":"7146_CR21","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/s41586-024-07948-2","volume":"638","author":"B Huang","year":"2025","unstructured":"Huang B, Abedi M, Ahn G, Coventry B, Sappington I, Tang C, et al. Designed endocytosis-inducing proteins degrade targets and amplify signals. Nature. 2025;638(8051):796\u2013804.","journal-title":"Nature"},{"issue":"5","key":"7146_CR22","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.1159\/000366361","volume":"34","author":"Z Tian","year":"2014","unstructured":"Tian Z, Yao G, Song H, Zhou Y, Geng J. IGF2R expression is associated with the chemotherapy response and prognosis of patients with advanced NSCLC. Cell Physiol Biochem. 2014;34(5):1578\u201388.","journal-title":"Cell Physiol Biochem"},{"key":"7146_CR23","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/234726","volume":"2012","author":"AH Lebastchi","year":"2012","unstructured":"Lebastchi AH, Kunstman JW, Carling T. Adrenocortical carcinoma: current therapeutic state-of-the-art. J Oncol. 2012;2012:234726.","journal-title":"J Oncol"},{"key":"7146_CR24","doi-asserted-by":"publisher","first-page":"613248","DOI":"10.3389\/fendo.2021.613248","volume":"12","author":"G Alyateem","year":"2021","unstructured":"Alyateem G, Nilubol N. Current status and future targeted therapy in adrenocortical cancer. Front Endocrinol (Lausanne). 2021;12:613248.","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"4","key":"7146_CR25","first-page":"626","volume":"40","author":"KM Schmainda","year":"2019","unstructured":"Schmainda KM, Prah MA, Hu LS, Quarles CC, Semmineh N, Rand SD, et al. Moving toward a consensus DSC-MRI protocol: validation of a low-flip angle single-dose option as a reference standard for brain tumors. AJNR Am J Neuroradiol. 2019;40(4):626\u201333.","journal-title":"AJNR Am J Neuroradiol"},{"issue":"5","key":"7146_CR26","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1016\/j.neuron.2014.01.015","volume":"81","author":"LT Hsieh","year":"2014","unstructured":"Hsieh LT, Gruber MJ, Jenkins LJ, Ranganath C. Hippocampal activity patterns carry information about objects in temporal context. Neuron. 2014;81(5):1165\u201378.","journal-title":"Neuron"},{"issue":"1","key":"7146_CR27","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1186\/s12935-022-02805-6","volume":"22","author":"Y Jin","year":"2022","unstructured":"Jin Y, Deng Z, Zhu T. Membrane protein trafficking in the anti-tumor immune response: work of endosomal-lysosomal system. Cancer Cell Int. 2022;22(1):413.","journal-title":"Cancer Cell Int"},{"key":"7146_CR28","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2022.5374","author":"X Zhang","year":"2022","unstructured":"Zhang X, Meng T, Cui S, Liu D, Pang Q, Wang P. Roles of ubiquitination in the crosstalk between tumors and the tumor microenvironment (review). Int J Oncol. 2022. https:\/\/doi.org\/10.3892\/ijo.2022.5374.","journal-title":"Int J Oncol"},{"key":"7146_CR29","doi-asserted-by":"crossref","unstructured":"Zhu XY, Liu WT, Hou XJ, Zong C, Yu W, Shen ZM, Qu SP, Tao M, Xue MM, Zhou DY, Bai HR, Gao L, Jiang JH, Zhao QD, Wei LX, Yang X, Han ZP, Zhang L. CD34(+)CLDN5(+) tumor associated senescent endothelial cells through IGF2-IGF2R signaling increased cholangiocellular phenotype in hepatocellular carcinoma, J Adv Res. 2024.","DOI":"10.1016\/j.jare.2024.12.008"},{"key":"7146_CR30","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000003645","author":"X Cai","year":"2025","unstructured":"Cai X, Sun R, Yang L, Yao N, Sun Y, Zhang G, et al. Proteomic analysis reveals modulation of key proteins in follicular thyroid cancer progression. Chin Med J (Engl). 2025. https:\/\/doi.org\/10.1097\/CM9.0000000000003645.","journal-title":"Chin Med J (Engl)"},{"issue":"8","key":"7146_CR31","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1038\/s41419-021-04053-4","volume":"12","author":"Z Zhang","year":"2021","unstructured":"Zhang Z, Mou Z, Xu C, Wu S, Dai X, Chen X, et al. Autophagy-associated circular RNA hsa_circ_0007813 modulates human bladder cancer progression via hsa-miR-361-3p\/IGF2R regulation. Cell Death Dis. 2021;12(8):778.","journal-title":"Cell Death Dis"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-07146-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-025-07146-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-07146-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T23:04:01Z","timestamp":1761087841000},"score":1,"resource":{"primary":{"URL":"https:\/\/translational-medicine.biomedcentral.com\/articles\/10.1186\/s12967-025-07146-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,21]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7146"],"URL":"https:\/\/doi.org\/10.1186\/s12967-025-07146-2","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,21]]},"assertion":[{"value":"2 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2025","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 that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interest"}}],"article-number":"1146"}}