Human Renal Normal, Tumoral, and Cancer Stem Cells Express Membrane-Bound Interleukin-15 Isoforms Displaying Different Functions.

Autor:	Azzi S; INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France., Gallerne C; INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France., Romei C; Department of Clinical and Experimental Immunology, Istituto G. Gaslini, Genoa, Italy., Le Coz V; INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France., Gangemi R; Biotherapy Unit, IRCCS A.O.U. San Martino-IST, Largo R. Benzi 10, Genoa, Italy., Khawam K; INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France., Devocelle A; INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France., Gu Y; Department of Oncology and Department of Experimental Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Bruno S; Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin, Italy., Ferrini S; Biotherapy Unit, IRCCS A.O.U. San Martino-IST, Largo R. Benzi 10, Genoa, Italy., Chouaib S; INSERM UMR 753, Université de Paris-Sud, Institut Gustave Roussy, Villejuif, France., Eid P; INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France., Azzarone B; Department of Clinical and Experimental Immunology, Istituto G. Gaslini, Genoa, Italy. Electronic address: bazzarone@hotmail.com., Giron-Michel J; INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France. Electronic address: julien.giron-michel@inserm.fr.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2015 Jun; Vol. 17 (6), pp. 509-17.
DOI:	10.1016/j.neo.2015.06.002
Abstrakt:	Intrarenal interleukin-15 (IL-15) participates to renal pathophysiology, but the role of its different membrane-bound isoforms remains to be elucidated. In this study, we reassess the biology of membrane-bound IL-15 (mb-IL-15) isoforms by comparing primary cultures of human renal proximal tubular epithelial cells (RPTEC) to peritumoral (ptumTEC), tumoral (RCC), and cancer stem cells (CSC/CD105(+)). RPTEC express a 14 to 16 kDa mb-IL-15, whose existence has been assumed but never formally demonstrated and likely represents the isoform anchored at the cell membrane through the IL-15 receptor α (IL-15Rα) chain, because it is sensitive to acidic treatment and is not competent to deliver a reverse signal. By contrast, ptumTEC, RCC, and CSC express a novel N-hyperglycosylated, short-lived transmembrane mb-IL-15 (tmb-IL-15) isoform around 27 kDa, resistant to acidic shock, delivering a reverse signal in response to its soluble receptor (sIL-15Rα). This reverse signal triggers the down-regulation of the tumor suppressor gene E-cadherin in ptumTEC and RCC but not in CSC/CD105(+), where it promotes survival. Indeed, through the AKT pathway, tmb-IL-15 protects CSC/CD105(+) from non-programmed cell death induced by serum starvation. Finally, both mb-IL-15 and tmb-IL-15 are sensitive to metalloproteases, and the cleaved tmb-IL-15 (25 kDa) displays a powerful anti-apoptotic effect on human hematopoietic cells. Overall, our data indicate that both mb-IL-15 and tmb-IL-15 isoforms play a complex role in renal pathophysiology downregulating E-cadherin and favoring cell survival. Moreover, "apparently normal" ptumTEC cells, sharing different properties with RCC, could contribute to organize an enlarged peritumoral "preneoplastic" environment committed to favor tumor progression. (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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