The ubiquitin-like molecule interferon-stimulated gene 15 is overexpressed in human prostate cancer

Abstract

Abstract.To identify molecules to serve as diagnostic markers for high-grade prostate cancer (PC) and targets for novel therapeutic drugs, we investigated the gene expression profiles of high-grade PCs using a cDNA microarray combined with laser microbeam microdissection. We subsequently confirmed that the ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) was expressed exclusively in high-grade PCs with high Gleason scores. Semi-quantitative reverse transcription PCR and immunohistochemical analysis confirmed the overexpression of ISG15, a 165 amino acid interferon-inducible ubiquitin-like protein, specifically in high-grade PCs with high Gleason scores 8-9, while it was not expressed in the normal prostate. Immunohistochemical analysis using anti-ISG15 polyclonal antibody confirmed an elevated expression of ISG15 protein in high-grade PCs as well as low-grade PCs compared with that in normal prostate (NP) epithelium. Knockdown of ISG15 expression by short interfering RNA (siRNA) in a PC cell line resulted in marked attenuation of PC cell survival; concordantly, ISG15 overexpression in a PC cell line promoted PC cell growth, indicating its oncogenic property. These findings suggest that ISG15 is involved in cell growth and survival of PCs and that it could be a potential molecular target for new therapeutics and a diagnostic biomarker for human PCs.

Interferon Stimulated Gene - ISG15 is a Potential Diagnostic Biomarker in Oral Squamous Cell Carcinomas

“…However, none of the molecules have had an expression level similar to the findings of present study. It is important to note that the oncogenic potential of ISG15 has been confirmed in vitro by overexpressing or knockdown of ISG15 in a prostrate cancer (PC) cell line that resulted in either an augmented or attenuated growth of PC cells respectively (Satake et al, 2010). As 80% of OSCC tumor tissue samples were found to overexpress ISG15, it is highly likely that the overexpression of this molecule may be used as a clinically relevant OSCC diagnostic biomarker.…”

ISG15 Is a Critical Microenvironmental Factor for Pancreatic Cancer Stem Cells

“…For example, while some reports suggest that like ubiquitylation, ISGylation may function in protein turnover (18), it may also play a previously unrecognized role in protein stability (17). The latter has been explored in systems of bladder, oral, prostate, and breast cancers, where high levels of ISG15 and its conjugates have been detected, suggesting a link between ISG15 and tumorigenesis (19)(20)(21)(22)(23)(24). For example, Kiessling and colleagues have shown that in prostate cancer, overexpression of UbE1L increased androgen receptor levels in an ISG15-dependent manner, implying that ISGylation promotes androgen receptor overexpression in cancer cells.…”

SNRPE is involved in cell proliferation and progression of high-grade prostate cancer through the regulation of androgen receptor expression

“…Plasmids designed to express short hairpin RNA (shRNA) were prepared by cloning doublestranded oligonucleotides into the pBAsi-h6 Neo vector (Takara Bio Inc., Shiga, Japan). The target sequences for SNRPE were as follows: sense strand sequence for siSNRPE: 5'-GCTCTATGAGCAAGTGAAT-3', and negative control EGFP siRNA (siEGFP): 5'-GAAGCAGCACGACTTCTTC-3' , as previously described (6). 22Rv1 cells (2x10 6 ) that highly expressed SNRPE were seeded in 10-cm dishes, transfected with pBA-siSNRPE or pBA-siEGFP using FuGENE6 (Roche Diagnostics) according to the manufacturer's instructions, and then cultured in the appropriate medium containing 800 µg/ml Geneticin (Sigma-Aldrich) for 14 days.…”

“…In a previous study, we analyzed the expression profiles of high-grade PC cells purified from clinically high-grade PC tissues with high PSA levels and high Gleason scores (6). Among the genes that were transactivated in the high-grade PC cells compared with normal prostatic epithelial cells, we focused on SNRPE in this study.…”

“…In a previous study, we analyzed the gene expression profiles of high-grade PC using a cDNA microarray combined with laser microbeam microdissection to enrich populations of cancer cells (6). In this study, among the genes that are transactivated in high-grade PC cells, we focused on small nuclear ribonucleoprotein polypeptide E (SNRPE) as a novel molecular target of treatment for PC, to validate SNRPE overexpression in clinically high-grade PC with a Gleason score of 8-10.…”