NLRP7 Enhances Choriocarcinoma Cell Survival and Camouflage in an Inflammasome Independent Pathway
Author:
Reynaud Déborah123, Alfaidy Nadia123ORCID, Collet Constance123, Lemaitre Nicolas123ORCID, Sergent Frederic123, Miege Céline123, Soleilhac Emmanuelle4, Assi Alaa Al5, Murthi Padma67ORCID, Courtois Gilles4, Fauvarque Marie-Odile4, Slim Rima8ORCID, Benharouga Mohamed123ORCID, Abi Nahed Roland1235ORCID
Affiliation:
1. Institut National de la Santé et de la Recherche Médicale U1292, Biologie et Biotechnologie pour la Santé, 38043 Grenoble, France 2. Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, 38054 Grenoble, France 3. Service Obstétrique, University Grenoble Alpes and Centre Hospitalo-Universitaire Grenoble Alpes, CS 10217, CEDEX 9, 38043 Grenoble, France 4. University Grenoble Alpes, Inserm, CEA, UA13 BGE, 38000 Grenoble, France 5. Laboratory of Fundamental and Applied Bioenergetics (LBFA), Univeristy Grenoble Alpes, Inserm, 38000 Grenoble, France 6. Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne VIC 3800, Australia 7. Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women’s Hospital, Parkville, VIC 3502, Australia 8. Departments of Human Genetics and Obstetrics and Gynecology, McGill University Health Centre Research Institute, Montréal, QC H4A 3J1, Canada
Abstract
Background: Gestational choriocarcinoma (GC) is a highly malignant trophoblastic tumor that often develops from a complete hydatidiform mole (HM). NLRP7 is the major gene responsible for recurrent HM and is involved in the innate immune response, inflammation and apoptosis. NLRP7 can function in an inflammasome-dependent or -independent pathway. Recently, we have demonstrated that NLRP7 is highly expressed in GC tumor cells and contributes to their tumorigenesis. However, the underlying mechanisms are still unknown. Here, we investigated the mechanism by which NLRP7 controls these processes in malignant (JEG-3) and non-tumor (HTR8/SVneo) trophoblastic cells. Cell survival, dedifferentiation, camouflage, and aggressiveness were compared between normal JEG-3 cells or knockdown for NLRP7, JEG-3 Sh NLRP7. In addition, HTR8/SVneo cells overexpressing NLRP7 were used to determine the impact of NLRP7 overexpression on non-tumor cells. NLRP7 involvement in tumor cell growth and tolerance was further characterized in vivo using the metastatic mouse model of GC. Results: We demonstrate that NLRP7 (i) functions in an inflammasome-dependent and -independent manners in HTR8/SVneo and JEG-3 cells, respectively; (ii) differentially regulates the activity of NF-κB in tumor and non-tumor cells; (iii) increases malignant cell survival, dedifferentiation, and camouflage; and (iv) facilitates tumor cells colonization of the lungs in the preclinical model of GC. Conclusions: This study demonstrates for the first time the mechanism by which NLRP7, independently of its inflammasome machinery, contributes to GC growth and tumorigenesis. The clinical relevance of NLRP7 in this rare cancer highlights its potential therapeutic promise as a molecular target to treat resistant GC patients.
Funder
Institut National de la Santé et de la Recherche Médicale (INSERM), University Grenoble-Alpes, VALO-GRAL CBH-EUR-GS Région Auvergne-Rhône-Alpes/Cancéropôle Lyon Auvergne Rhône-Alpes, Ligues Départementales (Isère & Savoie) contre le Cancer Fondation pour la Recherche Médicale GRAL, a program of the Chemistry Biology Health Graduate School of Université Grenoble Alpes
Reference53 articles.
1. ESMO Guidelines Working Group. Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up;Seckl;Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.,2013 2. Reynaud, D., Abi Nahed, R., Lemaitre, N., Bolze, P.A., Traboulsi, W., Sergent, F., Battail, C., Filhol, O., Sapin, V., and Boufettal, H. (2021). NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment. Cancers, 13. 3. Abi Nahed, R., Elkhoury Mikhael, M., Reynaud, D., Collet, C., Lemaitre, N., Michy, T., Hoffmann, P., Sergent, F., Marquette, C., and Murthi, P. (2022). Role of NLRP7 in Normal and Malignant Trophoblast Cells. Biomedicines, 10. 4. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans;Murdoch;Nat. Genet.,2006 5. NLRP7 is increased in human idiopathic fetal growth restriction and plays a critical role in trophoblast differentiation;Reynaud;J. Mol. Med.,2019
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|