FAS/FASL PATHWAY IS IMPAIRED IN CHORDOMA AND IS INVOLVED IN ZEBRAFISH (DANIO RERIO) NOTOCHORD DEVELOPMENT AND REGRESSION
Tesi di Dottorato
Data di Pubblicazione:
2013
Citazione:
FAS/FASL PATHWAY IS IMPAIRED IN CHORDOMA AND IS INVOLVED IN ZEBRAFISH (DANIO RERIO) NOTOCHORD DEVELOPMENT AND REGRESSION / L. Ferrari ; tutor: P. Riva ; supervisore: F. Cotelli ; supervisore: M. Miozzo ; coordinatore scuola di dottorato: G. Dehò. DIPARTIMENTO DI BIOTECNOLOGIE MEDICHE E MEDICINA TRASLAZIONALE, 2013 May 31. 25. ciclo, Anno Accademico 2012. [10.13130/ferrari-luca_phd2013-05-31].
Abstract:
Abstract
Chordoma is a rare malignant tumor characterized by chemoresistance and unforeseeable prognosis, originating from notochord remnants that do not disappear during development. The apoptotic mechanisms are fundamental for notochord cells development and regression, but little is known about the role of specific apoptotic pathways. At this purpose we investigated the possible implication of Fas/Fasl apoptotic pathway in chordoma tumorigenesis. FASL expression was absent, while both FAS anti- and pro-apoptotic isoforms were detected in most chordomas analyzed and in U-CH1 cells. These findings, besides the prevalent expression of inactive Caspases 8 and 3, suggest that Fas/Fasl pathway is impaired in this tumor. The enhancement of apoptosis in U-CH1 cells by treatment with soluble Fasl indicates that Fas/Fasl pathway can be activated in chordoma, suggesting Fas/Fasl as potential pharmacological targets. We also hypothesized that Fas/Fasl pathway dysregulation may have a role in chordoma onset. To unravel this issue we investigated the function of fas and fasl homologs in the zebrafish notochord development. We found that these genes were specifically expressed in notochord cells. Morpholino mediated knock-down of fas and fasl resulted in abnormal phenotypes mainly showing curved tail and altered motility. Notochord multi-cell-layer jumps instead of the typical “stack-of-coins” organization, larger vacuolated cells, defects in the peri-notochordal sheath structure and in vertebral mineralization have been detected in most morphants. In addition, we observed the persistent expression of ntla and col2a1a, the zebrafish homologs of the human T gene and COL2A1, which were found to be specifically upregulated in chordoma. In conclusion, our findings indicate that Fas/Fasl pathway activity can be enhanced in chordoma. Moreover, we demonstrated for the first time the involvement of fas and fasl in notochord development, differentiation and regression in zebrafish suggesting the implication of this pathway in chordoma onset.
Tipologia IRIS:
Tesi di dottorato
Keywords:
chordoma ; fas/fasl pathway ; zebrafish ; notochord
Elenco autori:
L. Ferrari
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