title: Human Renal Normal, Tumoral, and Cancer Stem Cells Express Membrane-Bound Interleukin-15 Isoforms Displaying Different Functions.
abstract: 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.
authors.affiliation: INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Azzi
authors.affiliation: INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Gallerne
authors.affiliation: Department of Clinical and Experimental Immunology, Istituto G. Gaslini, Genoa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Romei
authors.affiliation: INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Le Coz
authors.affiliation: Biotherapy Unit, IRCCS A.O.U. San Martino-IST, Largo R. Benzi 10, Genoa, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gangemi
authors.affiliation: INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France.
authors.forename: Krystel
authors.initials: K
authors.lastname: Khawam
authors.affiliation: INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Devocelle
authors.affiliation: Department of Oncology and Department of Experimental Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bruno
authors.affiliation: Biotherapy Unit, IRCCS A.O.U. San Martino-IST, Largo R. Benzi 10, Genoa, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.affiliation: INSERM UMR 753, Université de Paris-Sud, Institut Gustave Roussy, Villejuif, France.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.affiliation: INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Eid
authors.affiliation: Department of Clinical and Experimental Immunology, Istituto G. Gaslini, Genoa, Italy. Electronic address: bazzarone@hotmail.com.
authors.forename: Bruno
authors.initials: B
authors.lastname: Azzarone
authors.affiliation: INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France; Université Paris-Sud (Paris 11), Orsay, France. Electronic address: julien.giron-michel@inserm.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Giron-Michel
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms; D059016:Tumor Microenvironment
chemical_list: D019409:Interleukin-15; D020033:Protein Isoforms