FAS/FASL are dysregulated in chordoma and their loss-of-function impairs zebrafish notochord formation
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1Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università Degli Studi di Milano, Via Viotti 3/5 20133 Milan, Italy
2Dipartimento di Bioscienze, Università Degli Studi di Milano, Via Celoria 26 20133 Milan, Italy
3Dipartimento di Neurochirurgia, Università Vita-Salute IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy
4Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
5Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
* These authors contribute equally in this study.
Paola Riva, e-mail: email@example.com
Franco Cotelli, e-mail: firstname.lastname@example.org
Keywords: chordoma, FAS, FASL, notochord, zebrafish
Received: June 09, 2014 Accepted: June 21, 2014 Published: July 01, 2014
Chordoma is a rare malignant tumor that recapitulates the notochord phenotype and is thought to derive from notochord remnants not correctly regressed during development. Apoptosis is necessary for the proper notochord development in vertebrates, and the apoptotic pathway mediated by Fas and Fasl has been demonstrated to be involved in notochord cells regression. This study was conducted to investigate the expression of FAS/FASL pathway in a cohort of skull base chordomas and to analyze the role of fas/fasl homologs in zebrafish notochord formation. FAS/FASL expression was found to be dysregulated in chordoma leading to inactivation of the downstream Caspases in the samples analyzed. Both fas and fasl were specifically expressed in zebrafish notochord sorted cells. fas and fasl loss-of-function mainly resulted in larvae with notochord multi-cell-layer jumps organization, larger vacuolated notochord cells, defects in the peri-notochordal sheath structure and in vertebral mineralization. Interestingly, we observed the persistent expression of ntla and col2a1a, the zebrafish homologs of the human T gene and COL2A1 respectively, which are specifically up-regulated in chordoma. These results demonstrate for the first time the dysregulation of FAS/FASL in chordoma and their role in notochord formation in the zebrafish model, suggesting their possible implication in chordoma onset.
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