ABSTRACT Cellular inhibitor of apoptosis-1 (cIAP1) is a signaling regulator with oncogenic properties. It is involved in the regulation of signaling pathways controlling inflammation, cell

survival, proliferation, differentiation and motility. It is recruited into membrane-receptor-associated signaling complexes thanks to the molecular adaptor TRAF2. However, the cIAP1/TRAF2

complex exists, independently of receptor engagement, in several subcellular compartments. The present work strengthens the importance of TRAF2 in the oncogenic properties of cIAP1.

cIAPs-deficient mouse embryonic fibroblasts (MEFs) were transformed using the HRas-V12 oncogene. Re-expression of cIAP1 enhanced tumor growth in a nude mice xenograft model, and promoted

subunits of a signaling complex promoting a pro-tumoral signal. cIAP1/TRAF2 promoted the activation of the canonical NF-κB and ERK1/2 signaling pathways. NF-κB-dependent production of IL-6

triggered the activation of the JAK/STAT3 axis in an autocrine manner. Inhibition or downregulation of STAT3 specifically compromised the growth of cIAP1-restored MEFs but not that of MEFs

expressing a cIAP1-mutant and treating mice with the STAT3 inhibitor niclosamide completely abrogated cIAP1/TRAF2-mediated tumor growth. Altogether, we demonstrate that cIAP1/TRAF2 binding

is essential to promote tumor growth via the activation of the JAK/STAT3 signaling pathway. Access through your institution Buy or subscribe This is a preview of subscription content, access

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Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS IKKΑ PROMOTES LUNG ADENOCARCINOMA GROWTH THROUGH ERK

SIGNALING ACTIVATION VIA DARPP-32-MEDIATED INHIBITION OF PP1 ACTIVITY Article Open access 25 March 2023 TRIM22 ACTIVATES NF-ΚB SIGNALING IN GLIOBLASTOMA BY ACCELERATING THE DEGRADATION OF

IΚBΑ Article Open access 19 August 2020 TRAIL-RECEPTOR 2—A NOVEL NEGATIVE REGULATOR OF P53 Article Open access 31 July 2021 DATA AVAILABILITY Figshare

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Scholar  Download references ACKNOWLEDGEMENTS We thank Pauline Maes from the CLIPP proteomic platform, University of Burgundy, Philippe Hammann from the Strasbourg proteomic platform, IBMC,

Valérie Saint-Gorgio from zootechny center, University of Burgundy, and Romain Aucagne from the Crigen platform, University of Burgundy. This work was supported by grants from the ‘Comités

de Côte d’Or et de l’Yonne’ of the ‘Ligue Contre le Cancer’ (LD), La Ligue Nationale contre le Cancer (CG’s team), the European Union and the ‘Conseil Régional de Bourgogne’, a French

Government grant managed by the French National Research Agency under the program ‘Investissements d’Avenir’ with reference ANR-11-LABX-0021, and fellowships from the ‘Ministère de

l’Enseignement Supérieur et de la Recherche’ of France (to BD, AZ, JB and JA), the ‘Fondation ARC pour la Recherche sur le Cancer’ (to BD). We thank the FEDER for their financial support.

AUTHOR INFORMATION Author notes * Jean Berthelet Present address: Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia * These authors contributed equally: Baptiste

Dumétier, Aymeric Zadoroznyj. AUTHORS AND AFFILIATIONS * Institut National de la Santé et de la Recherche Médicale (Inserm), LNC UMR1231, LabEx LIpSTIC, Team with the label of excellence

from «la ligue national contre le Cancer», 21000, Dijon, France Baptiste Dumétier, Aymeric Zadoroznyj, Jean Berthelet, Sébastien Causse, Jennifer Allègre, Pauline Bourgeois, Florine Cattin, 

Carmen Garrido & Laurence Dubrez * Université de Bourgogne-Franche-Comté, 21000, Dijon, France Baptiste Dumétier, Aymeric Zadoroznyj, Jean Berthelet, Sébastien Causse, Jennifer Allègre, 

Pauline Bourgeois, Florine Cattin, Carmen Garrido & Laurence Dubrez * LIIC, EA7269, Université de Bourgogne-Franche-Comté, 21000, Paris, France Cindy Racoeur & Catherine Paul *

Laboratory of Immunology and Immunotherapy of Cancers, EPHE, PSL Research University, 75000, Paris, France Cindy Racoeur & Catherine Paul * Anticancer Center Georges François

Leclerc-Unicancer, Dijon, France Carmen Garrido Authors * Baptiste Dumétier View author publications You can also search for this author inPubMed Google Scholar * Aymeric Zadoroznyj View

author publications You can also search for this author inPubMed Google Scholar * Jean Berthelet View author publications You can also search for this author inPubMed Google Scholar *

Sébastien Causse View author publications You can also search for this author inPubMed Google Scholar * Jennifer Allègre View author publications You can also search for this author inPubMed

 Google Scholar * Pauline Bourgeois View author publications You can also search for this author inPubMed Google Scholar * Florine Cattin View author publications You can also search for

this author inPubMed Google Scholar * Cindy Racoeur View author publications You can also search for this author inPubMed Google Scholar * Catherine Paul View author publications You can

also search for this author inPubMed Google Scholar * Carmen Garrido View author publications You can also search for this author inPubMed Google Scholar * Laurence Dubrez View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS BD and AZ performed most of the experiments and analyzed the data. JB initiated the project,

established the tumor model, and performed some in vivo experiments. SC performed immunofluorescence analysis. JA, PB, and FC helped in performing western blots, clonogenicity assays, and in

vivo experiments. CR and CP brought expertise in in vivo model and performed IV injection. CG provided scientific expertise and corrected the paper and LD conceived and supervised the

project, conducted the GEPIA analysis, analyzed the data and interpreted the results, wrote the paper with input from all authors. CORRESPONDING AUTHOR Correspondence to Laurence Dubrez.

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Dumétier, B., Zadoroznyj, A., Berthelet, J. _et al._ cIAP1/TRAF2 interplay promotes tumor growth through the activation of STAT3. _Oncogene_ 42, 198–208 (2023).

https://doi.org/10.1038/s41388-022-02544-y Download citation * Received: 10 March 2022 * Revised: 26 October 2022 * Accepted: 04 November 2022 * Published: 18 November 2022 * Issue Date: 12

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