{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T19:03:49Z","timestamp":1772219029594,"version":"3.50.1"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute of the National Institutes of Health","award":["U54CA168512"],"award-info":[{"award-number":["U54CA168512"]}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["CA210874"],"award-info":[{"award-number":["CA210874"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA016058"],"award-info":[{"award-number":["P30CA016058"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Effective therapies for retroperitoneal (RP) dedifferentiated liposarcoma (DDLPS) remain unavailable. Loco-regional recurrence occurs in &gt;80% of cases; 5-year disease-specific survival is only 20%. DDLPS is especially prevalent in the retroperitoneum and abdomen; evaluation of the DDLPS microenvironment in these high-fat compartments appears pertinent. Adipose is a main supplier of interleukin-6 (IL6); excessive activation of IL6 signal transducer glycoprotein 130 (GP130) underlies the development of some diseases. The role of GP130 pathway activation remains unstudied in DDLPS, so we examined the role of microenvironment fat cell activation of the IL6\/GP130 signaling cascade in DDLPS. All DDLPS tumors and cell lines studied expressed elevated levels of the GP130-encoding gene\n                    <jats:italic>IL6ST<\/jats:italic>\n                    and GP130 protein compared to normal tissue and cell line controls. IL6 increased DDLPS cell growth and migration, possibly through increased signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) activation, and upregulated mouse double minute 2 (MDM2). GP130 loss conveyed opposite effects; pharmacological blockade of GP130 by SC144 produced the MDM2 splice variant MDM2-ALT1, known to inhibit full length MDM2 (MDM2-FL). Although genomic\n                    <jats:italic>MDM2<\/jats:italic>\n                    amplification is pathognomonic for DDLPS, mechanisms driving MDM2 expression, regulation, and function beyond the MDM2:p53 negative feedback loop are poorly understood. Our findings suggest a novel preadipocyte DDLPS-promoting role due to IL6 release, via upregulation of DDLPS MDM2 expression. Pharmacological GP130 blockade reduced the IL6-induced increase in DDLPS MDM2 mRNA and protein levels, possibly through enhanced expression of MDM2-ALT1, a possibly targetable pathway with potential as future DDLPS patient therapy.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0299962","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T17:39:57Z","timestamp":1758130797000},"page":"e0299962","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Blockade of interleukin-6 (IL-6) signaling in dedifferentiated liposarcoma (DDLPS) decreases mouse double minute 2 (MDM2) oncogenicity via alternative splicing"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6283-0216","authenticated-orcid":true,"given":"Abeba","family":"Zewdu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danielle","family":"Braggio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gonzalo","family":"Lopez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kara","family":"Batte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Safiya","family":"Khurshid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernanda","family":"Costas C. de Faria","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hemant K.","family":"Bid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Koller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Casadei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine J.","family":"Ladner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8574-0715","authenticated-orcid":true,"given":"Valerie","family":"Grignol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"O. Hans","family":"Iwenofu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawn","family":"Chandler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis C.","family":"Guttridge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0443-1583","authenticated-orcid":true,"given":"Raphael E.","family":"Pollock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"issue":"11","key":"pone.0299962.ref001","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/S1470-2045(12)70474-6","article-title":"Effect of the MDM2 antagonist RG7112 on the p53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study","volume":"13","author":"I Ray-Coquard","year":"2012","journal-title":"Lancet Oncol"},{"issue":"9","key":"pone.0299962.ref002","doi-asserted-by":"crossref","first-page":"2638","DOI":"10.1158\/1078-0432.CCR-11-3203","article-title":"The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial","volume":"18","author":"JJ Luke","year":"2012","journal-title":"Clin Cancer Res"},{"issue":"4","key":"pone.0299962.ref003","first-page":"392","article-title":"Current treatment of soft tissue sarcoma","volume":"21","author":"S Steen","year":"2008","journal-title":"Proc (Bayl Univ Med Cent)"},{"issue":"3","key":"pone.0299962.ref004","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1097\/00000478-199703000-00002","article-title":"Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation","volume":"21","author":"WH Henricks","year":"1997","journal-title":"Am J Surg Pathol"},{"issue":"3","key":"pone.0299962.ref005","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1245\/s10434-008-0250-2","article-title":"Establishing prognosis in retroperitoneal sarcoma: a new histology-based paradigm","volume":"16","author":"DA Anaya","year":"2009","journal-title":"Ann Surg Oncol"},{"issue":"3","key":"pone.0299962.ref006","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1093\/annonc\/mdt577","article-title":"Retroperitoneal sarcomas: patterns of care at diagnosis, prognostic factors and focus on main histological subtypes: a multicenter analysis of the French Sarcoma Group","volume":"25","author":"M Toulmonde","year":"2014","journal-title":"Ann Oncol"},{"issue":"1","key":"pone.0299962.ref007","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.ijrobp.2006.08.025","article-title":"Retroperitoneal soft tissue sarcoma: an analysis of radiation and surgical treatment","volume":"67","author":"MT Ballo","year":"2007","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"14","key":"pone.0299962.ref008","doi-asserted-by":"crossref","first-page":"3846","DOI":"10.1158\/0008-5472.CAN-16-2984","article-title":"Exosome-derived miR-25-3p and miR-92a-3p stimulate liposarcoma progression","volume":"77","author":"L Casadei","year":"2017","journal-title":"Cancer Res"},{"issue":"12","key":"pone.0299962.ref009","first-page":"4196","article-title":"Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo","volume":"82","author":"V Mohamed-Ali","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"pone.0299962.ref010","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1007\/s00125-004-1403-x","article-title":"Interleukin-6 and tumor necrosis factor-alpha are not increased in patients with Type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness","volume":"47","author":"AL Carey","year":"2004","journal-title":"Diabetologia"},{"issue":"3","key":"pone.0299962.ref011","first-page":"847","article-title":"Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid","volume":"83","author":"SK Fried","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"pone.0299962.ref012","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1093\/asj\/sjv194","article-title":"Interaction between breast cancer cells and adipose tissue cells derived from fat grafting","volume":"36","author":"M Massa","year":"2016","journal-title":"Aesthet Surg J"},{"key":"pone.0299962.ref013","doi-asserted-by":"crossref","first-page":"10230","DOI":"10.1038\/ncomms10230","article-title":"Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity","volume":"7","author":"V Laurent","year":"2016","journal-title":"Nat Commun"},{"issue":"2","key":"pone.0299962.ref014","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.cell.2009.12.052","article-title":"Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression","volume":"140","author":"EJ Park","year":"2010","journal-title":"Cell"},{"issue":"4","key":"pone.0299962.ref015","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1210\/er.2010-0030","article-title":"Paracrine and endocrine effects of adipose tissue on cancer development and progression","volume":"32","author":"J Park","year":"2011","journal-title":"Endocr Rev"},{"issue":"10","key":"pone.0299962.ref016","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1093\/jn\/134.10.2673","article-title":"Expression of interleukin-6 is greater in preadipocytes than in adipocytes of 3T3-L1 cells and C57BL\/6J and ob\/ob mice","volume":"134","author":"JM Harkins","year":"2004","journal-title":"J Nutr"},{"issue":"11","key":"pone.0299962.ref017","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1016\/j.bbamcr.2009.07.009","article-title":"Cytokine signalling via gp130 in gastric cancer","volume":"1793","author":"M Howlett","year":"2009","journal-title":"Biochim Biophys Acta"},{"issue":"4","key":"pone.0299962.ref018","doi-asserted-by":"crossref","first-page":"439","DOI":"10.4172\/2155-9899.1000439","article-title":"Interleukin-6: a constitutive modulator of glycoprotein 130, neuroinflammatory and cell survival signaling in retina","volume":"7","author":"FD Echevarria","year":"2016","journal-title":"J Clin Cell Immunol"},{"issue":"22","key":"pone.0299962.ref019","doi-asserted-by":"crossref","first-page":"12991","DOI":"10.1074\/jbc.271.22.12991","article-title":"Differential activation of acute phase response factor\/STAT3 and STAT1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. I. Definition of a novel phosphotyrosine motif mediating STAT1 activation","volume":"271","author":"C Gerhartz","year":"1996","journal-title":"J Biol Chem"},{"issue":"5","key":"pone.0299962.ref020","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1002\/hep.510300522","article-title":"Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line","volume":"30","author":"J Park","year":"1999","journal-title":"Hepatology"},{"issue":"42","key":"pone.0299962.ref021","doi-asserted-by":"crossref","first-page":"5991","DOI":"10.1038\/sj.onc.1204833","article-title":"Biologic sequelae of interleukin-6 induced PI3-K\/Akt signaling in multiple myeloma","volume":"20","author":"T Hideshima","year":"2001","journal-title":"Oncogene"},{"issue":"2","key":"pone.0299962.ref022","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1161\/ATVBAHA.111.229435","article-title":"Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice","volume":"32","author":"H Schuett","year":"2012","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"pone.0299962.ref023","article-title":"IL-6 trans-signaling links inflammation with angiogenesis in the peritoneal membrane","author":"R Catar","year":"2016","journal-title":"J Am Soc Nephrol"},{"issue":"6","key":"pone.0299962.ref024","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1158\/1535-7163.MCT-12-1082","article-title":"Discovery of a novel orally active small-molecule gp130 inhibitor for the treatment of ovarian cancer","volume":"12","author":"S Xu","year":"2013","journal-title":"Mol Cancer Ther"},{"issue":"2","key":"pone.0299962.ref025","doi-asserted-by":"crossref","DOI":"10.3390\/ijms24021342","article-title":"FISH diagnostic assessment of MDM2 amplification in liposarcoma: potential pitfalls and troubleshooting recommendations","volume":"24","author":"A Gambella","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"19","key":"pone.0299962.ref026","doi-asserted-by":"crossref","first-page":"9502","DOI":"10.1158\/0008-5472.CAN-05-4271","article-title":"Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4","volume":"66","author":"DS Chandler","year":"2006","journal-title":"Cancer Res"},{"issue":"19","key":"pone.0299962.ref027","doi-asserted-by":"crossref","first-page":"9467","DOI":"10.1158\/0008-5472.CAN-05-3013","article-title":"Regulation of hdm2 by stress-induced hdm2alt1 in tumor and nontumorigenic cell lines correlating with p53 stability","volume":"66","author":"CS Dias","year":"2006","journal-title":"Cancer Res"},{"issue":"8","key":"pone.0299962.ref028","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0104444","article-title":"Stress-induced alternative splice forms of MDM2 and MDMX modulate the p53-pathway in distinct ways","volume":"9","author":"AG Jacob","year":"2014","journal-title":"PLoS One"},{"issue":"3","key":"pone.0299962.ref029","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/labinvest.2010.185","article-title":"An experimental model for the study of well-differentiated and dedifferentiated liposarcoma; deregulation of targetable tyrosine kinase receptors","volume":"91","author":"T Peng","year":"2011","journal-title":"Lab Invest"},{"issue":"5","key":"pone.0299962.ref030","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1158\/1078-0432.CCR-15-1522","article-title":"SAR405838: a novel and potent inhibitor of the MDM2:p53 axis for the treatment of dedifferentiated liposarcoma","volume":"22","author":"KLJ Bill","year":"2016","journal-title":"Clin Cancer Res"},{"issue":"8","key":"pone.0299962.ref031","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/nm0896-912","article-title":"Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer","volume":"2","author":"I Sigalas","year":"1996","journal-title":"Nat Med"},{"issue":"2","key":"pone.0299962.ref032","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ccr.2009.01.001","article-title":"IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer","volume":"15","author":"S Grivennikov","year":"2009","journal-title":"Cancer Cell"},{"issue":"11","key":"pone.0299962.ref033","article-title":"Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine\/paracrine stimulation of the interleukin 6\/gp130 cytokine system","volume":"63","author":"V Sriuranpong","year":"2003","journal-title":"Cancer Res"},{"issue":"7","key":"pone.0299962.ref034","doi-asserted-by":"crossref","first-page":"631","DOI":"10.2174\/1568009615666150916093110","article-title":"Persistent GP130\/STAT3 signaling contributes to the resistance of doxorubicin, cisplatin, and MEK inhibitor in human rhabdomyosarcoma cells","volume":"16","author":"X Wu","year":"2016","journal-title":"Curr Cancer Drug Targets"},{"issue":"1","key":"pone.0299962.ref035","doi-asserted-by":"crossref","DOI":"10.1158\/1078-0432.CCR-04-1752","article-title":"Persistent activation of STAT3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells","volume":"12","author":"T Gritsko","year":"2006","journal-title":"Clin Cancer Res"},{"issue":"9","key":"pone.0299962.ref036","first-page":"691","article-title":"Chemotherapy resistance induced by interleukin-6 in ovarian cancer cells and its signal transduction pathways","volume":"45","author":"Y Wang","year":"2010","journal-title":"Zhonghua Fu Chan Ke Za Zhi"},{"key":"pone.0299962.ref037","doi-asserted-by":"crossref","first-page":"5218","DOI":"10.1038\/ncomms6218","article-title":"LIF negatively regulates tumour-suppressor p53 through Stat3\/ID1\/MDM2 in colorectal cancers","volume":"5","author":"H Yu","year":"2014","journal-title":"Nat Commun"},{"issue":"1","key":"pone.0299962.ref038","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.bmc.2006.09.073","article-title":"Synthesis and antitumor activities of a series of novel quinoxalinhydrazides","volume":"15","author":"F Grande","year":"2007","journal-title":"Bioorg Med Chem"},{"issue":"9","key":"pone.0299962.ref039","article-title":"MDM2 induces NF-\u03baB\/p65 expression transcriptionally through Sp1-binding sites: a novel, p53-independent role of MDM2 in doxorubicin resistance in acute lymphoblastic leukemia","volume":"99","author":"L Gu","year":"2002","journal-title":"Blood"},{"issue":"19","key":"pone.0299962.ref040","article-title":"PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells","volume":"63","author":"M Zhou","year":"2003","journal-title":"Cancer Res"},{"issue":"4","key":"pone.0299962.ref041","doi-asserted-by":"crossref","DOI":"10.1038\/cddis.2011.33","article-title":"Disruption of the MDM2-p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas\/FasL pathway","volume":"2","author":"R Koster","year":"2011","journal-title":"Cell Death Dis"},{"issue":"6","key":"pone.0299962.ref042","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1093\/annonc\/mdr485","article-title":"Advanced well-differentiated\/dedifferentiated liposarcomas: role of chemotherapy and survival","volume":"23","author":"A Italiano","year":"2012","journal-title":"Ann Oncol"},{"issue":"7","key":"pone.0299962.ref043","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1200\/JCO.1995.13.7.1537","article-title":"Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group","volume":"13","author":"A Santoro","year":"1995","journal-title":"J Clin Oncol"},{"issue":"30","key":"pone.0299962.ref044","doi-asserted-by":"crossref","first-page":"4041","DOI":"10.1038\/sj.onc.1204533","article-title":"An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2","volume":"20","author":"SC Evans","year":"2001","journal-title":"Oncogene"},{"issue":"7","key":"pone.0299962.ref045","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0180297","article-title":"Repositioning Bazedoxifene as a novel IL-6\/GP130 signaling antagonist for human rhabdomyosarcoma therapy","volume":"12","author":"H Xiao","year":"2017","journal-title":"PLoS One"},{"issue":"2","key":"pone.0299962.ref046","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s00432-016-2284-3","article-title":"Stromal factors involved in human prostate cancer development, progression and castration resistance","volume":"143","author":"N Eiro","year":"2017","journal-title":"J Cancer Res Clin Oncol"},{"issue":"3","key":"pone.0299962.ref047","article-title":"Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism","volume":"12","author":"J Lee","year":"2017","journal-title":"PLoS One"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0299962","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T17:40:09Z","timestamp":1758130809000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0299962"}},"subtitle":[],"editor":[{"given":"Chien-Feng","family":"Li,","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,17]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0299962","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.02.21.581397","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,17]]}}}