ISG15 as a prognostic biomarker in solitary fibrous tumour

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

STAT6-targeting antisense oligonucleotides against solitary fibrous tumor

“…In addition to the development of an IEC139 PDX mouse model (see “ materials and methods / generation of IEC139 PDX mouse model ”) we also established a matching IEC139 primary SFT cell line ( Table 1 ). 50 To identify the NAB2-STAT6 fusion type of the IEC139 PDX model, total RNA was extracted from resected PDX tumor samples and subjected to RT-PCR and Sanger sequencing using primers specific to the fusion type (forward primer P18: within exon 6 of NAB2; reverse primer P19: within exon 16 of STAT6). As shown in Figures 4 A and 4B, the IEC139 cell line and the corresponding PDX samples were confirmed to have a NAB2exon6-STAT6exon16 fusion type (breakpoint between NAB2 exon 6: 5′-CACCTCTCGCAG-3′ and STAT6 exon 16: 5′-GCTCTCCAC-3′, highlighted in blue).…”

Reduction of Tumor Growth with RNA-Targeting Treatment of the NAB2–STAT6 Fusion Transcript in Solitary Fibrous Tumor Models

“…Lastly, the ex vivo efficacy of our NAB2–STAT6 fusion-targeting CRISPR/CasRx system was evaluated using a xenograft model, which may not fully capture the pathological demonstrations of SFT. Thus, in future studies, we plan to reassess candidate RNA-based therapeutics (ASOs and CRISPR/CasRx) using our recently developed SFT PDX (patient-derived xenograft) model [ 60 ], and additionally explore the combinations of ASOs and CRISPR/CasRx for their potential synergistic therapeutic effects.…”

Advances in transcriptomics and proteomics in differentiated thyroid cancer: An updated perspective (Review)

“…Jin et al (67) studied PTMC with and without LNM and screened for proteins potentially associated with migration and invasion, such as α-1-antitrypsin, α-actinin-1, carbonic anhydrase 4, high mobility group protein HMGI-C and hepatocellular carcinoma-derived growth factor. ISG15 ubiquitin like modifier (ISG15), a type I interferon-regulated ubiquitin-like molecule that plays crucial roles in modulating cell growth and cancer progression, has been reported to be highly expressed in various cancers (68)(69)(70)(71). Similarly, ISG15 was well distinguished between patients with lymph node metastatic and non-metastatic PTMC.…”