Abstract
Interferon-Stimulated Gene 15 (ISG15), an antagonist of the canonical ubiquitin pathway, is frequently overexpressed in various cancers. In cancer cells, ISG15 is detected as free (intracellular) and conjugated to cellular proteins (ISGylation). Free ISG15 is also secreted into the extracellular milieu. ISGylation has protumor functions and extracellular free ISG15 has immunomodulatory properties in vitro. Therefore, whether ISG15 is a tumor suppressor or tumor promoter in vivo remains controversial. The current study aimed to clarify the role of free ISG15 in tumorigenesis. Breast cancer cells stably expressing control, ISG15, and UbcH8 (ISG15-specific E2 ligase) shRNAs were used to assess the immunoregulatory and antitumor function of free ISG15 in cell culture (in vitro) and in nude mice (in vivo). We show that extracellular free ISG15 suppresses breast tumor growth and increases NK cell infiltration into xenografted breast tumors in nude mice, and intracellular free ISG15 enhances major histocompatibility complex (MHC) class I surface expression in breast cancer cells. We conclude that free ISG15 may have antitumor and immunoregulatory function in vivo. These findings provides the basis for developing strategies to increase systemic levels of free ISG15 to treat cancer patients overexpressing the ISG15 pathway.
Highlights
Interferon-Stimulated Gene 15 (ISG15) has emerged as a promising and novel oncoprotein biomarker elevated in various cancers [1,2,3]
To test whether ISG15 contributes to tumorigenesis in vivo, we examined the ability of the ZR-75-1 breast cancer cells constitutively overexpressing ISG15 (ZR/ control shRNA) and ZR-75-1 cells silenced for ISG15 expression (ZR/ISG15 shRNA), described in [13, 20], to form tumors in nude mice (Ncrnu/nu, Jackson Laboratory)
Because constitutive ISG15 induction confers a malignant phenotype on breast cancer cells [13, 14], we anticipated that ZR/control shRNA cells overexpressing ISG15 would form large tumors compared to the ZR/ISG15 shRNA cells silenced for the ISG15 expression
Summary
Interferon-Stimulated Gene 15 (ISG15) has emerged as a promising and novel oncoprotein biomarker elevated in various cancers [1,2,3]. Whether ISG15 promotes or suppresses tumor growth in vivo remains controversial. ISG15 was the first ubiquitin-like protein identified and is comprised of two ubiquitin-like β-grasp domains connected by a linker region [7]. The presence of a canonical ubiquitin C-terminal LRLRGG sequence very early suggested that the polypeptide exerted its biological effects through covalent conjugation to cellular protein targets [7], later confirmed by Western blot [8] and immunohistochemistry [9]. ISG15 exists in both free and conjugated pools within cells, both of which are often elevated in cancer, the basis for differences in cellular levels among different tumors remains unclear [12]
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