RT Journal Article
T1 ISG15 as a prognostic biomarker in solitary fibrous tumour.
A1 Mondaza-Hernandez, Jose L
A1 Moura, David S
A1 Lopez-Alvarez, María
A1 Sanchez-Bustos, Paloma
A1 Blanco-Alcaina, Elena
A1 Castilla-Ramirez, Carolina
A1 Collini, Paola
A1 Merino-Garcia, Jose
A1 Zamora, Jorge
A1 Carrillo-Garcia, Jaime
A1 Maestro, Roberta
A1 Hindi, Nadia
A1 Garcia-Foncillas, Jesus
A1 Martin-Broto, Javier
K1 Biomarker
K1 Cancer stem cell
K1 Drug resistance
K1 ISG15
K1 Solitary fibrous tumour
AB Solitary fibrous tumour (SFT) is a rare mesenchymal malignancy that lacks robust prognostic and predictive biomarkers. Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like modifier, associated with tumour progression, and with poor survival of SFT patients, as previous published by our group. Here, we describe the role of ISG15 in the biology of this rare tumour. ISG15 expression was assessed by immunohistochemistry in tissue microarrays from SFT patients and tested for correlation with progression-free survival and overall survival (OS). The effects of ISG15 knockdown or induction were investigated for cancer stem cell (CSC) characteristics and for drug sensitivity in unique in vitro models of SFT. The prognostic value of ISG15 for OS was validated at protein level in malignant SFT patients, prospectively treated with pazopanib and enrolled in GEIS-32 trial. In SFT in vitro models, ISG15 knockdown lead to a decrease in the expression of CSC-related genes, including SOX2, NANOG, ALDH1A1, ABCB1 and ABCC1. Likewise, ISG15 downregulation decreased the clonogenic/ tumoursphere-forming ability of SFT cells, while enhancing apoptotic cell death after doxorubicin, pazopanib or trabectedin treatment in 3D cell cultures. The regulation of CSC-related genes by ISG15 was confirmed after inducing its expression with interferon-β1; ISG15 induction upregulated 1.28- to 451-fold the expression of CSC-associated genes. ISG15 is a prognostic factor in malignant SFT, regulating the expression of CSC-related genes and CSCs maintenance. Our results suggest that ISG15 could be a novel therapeutic target in SFT, which could improve the efficacy of the currently available treatments.
YR 2022
FD 2022-07-21
LK http://hdl.handle.net/10668/19520
UL http://hdl.handle.net/10668/19520
LA en
DS RISalud
RD Apr 8, 2025