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Updated: Aug 7, 2025
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
ISG15 is a potential therapeutic target for osteosarcoma: a comprehensive analysis based on bioinformatics and in
Yedan Liao1,2, Xueqi Zhang2, Jiadai Tang2
1Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center) Kunming, Yunnan, China.
Background:
The expression of aberrant interferon-stimulated gene 15 (ISG15) is connected with various human diseases, including cancer. ISG15 is involved in tumor formation and metastasis. However, its role in osteosarcoma is uncertain.
Methods:
ISG15 expression in pan-cancer from RNA Sequencing data were obtained from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases. The relationship between ISG15 expression and prognosis was assessed through TCGA clinical survival data. Immunohistochemistry (IHC) images of ISG15 were retrieved using the Human Protein Atlas to analyze the differences in selected normal and tumor tissues. Gene enrichment analysis and signaling pathway analysis were used to assess the potential role of ISG15 in sarcoma, and the correlation between ISG15 expressions and immune cell infiltration levels was estimated by immune infiltration analysis. The expression levels of ISG15 were assessed by qRT-PCR and IHC. Colony formation, wound healing assay and transwell assay were used to detect the effects of ISG15 on the biological behaviors of osteosarcoma cells. The correlation between ISG15 levels and CD8+/CD68+ cells was further examined by double-labeled immunofluorescence. The chemotactic effect of ISG15 on CD8+/CD68+ cells was demonstrated by chemotactic experiments and flow cytometry.
Results:
ISG15 was highly expressed in most cancers, while high ISG15 expression was significantly correlated with poor overall survival. Gene enrichment analysis in sarcoma suggested that antigen processing and presentation might be involved in the oncogenic mechanism of ISG15. Further immune infiltration analysis showed that high ISG15 expression might reflect the infiltration level of certain immune cells. Additionally, our verification showed that ISG15 was significantly related to the occurrence and metastasis of osteosarcoma, and knockdown of ISG15 significantly altered cell biological behavior, resulting in decreased proliferation, migration and invasion capabilities of osteosarcoma cells. The high expression of ISG15 in osteosarcoma tissue was associated with a high level of CD68+ immune cell infiltration while a low level of CD8+ T cell infiltration. CD68+ immune cells were recruited in vitro by overexpression of ISG15, which on the contrary could weaken the chemotaxis of CD8+ T cells.
Conclusion:
High ISG15 expression is an inherent feature of osteosarcoma and triggers tumorigenesis and metastasis by regulating tumor immunogenicity. ISG15 is expected to be the target of osteosarcoma treatment.
Insights
Aberrant interferon-stimulated gene 15 (ISG15) expression drives osteosarcoma growth and metastasis by altering tumor immunity. Targeting ISG15 may offer a novel therapeutic strategy for osteosarcoma patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Aberrant expression of interferon-stimulated gene 15 (ISG15) is linked to various cancers, influencing tumor formation and metastasis.
- The specific role of ISG15 in osteosarcoma pathogenesis remains unclear, necessitating further investigation.
Purpose of the Study:
- To investigate the expression patterns and prognostic significance of ISG15 in osteosarcoma.
- To elucidate the functional role of ISG15 in osteosarcoma cell behavior and its impact on the tumor immune microenvironment.
Main Methods:
- Analyzed pan-cancer ISG15 expression and survival data from TCGA and GTEx.
- Utilized immunohistochemistry (IHC) and qRT-PCR to assess ISG15 levels in osteosarcoma tissues.
- Performed in vitro assays (colony formation, wound healing, Transwell) to evaluate ISG15's effect on cell proliferation, migration, and invasion.
- Investigated the correlation between ISG15 expression and immune cell infiltration (CD8+, CD68+) using immunofluorescence and chemotaxis assays.
Main Results:
- High ISG15 expression was observed in most cancers and correlated with poor prognosis.
- ISG15 knockdown significantly reduced osteosarcoma cell proliferation, migration, and invasion.
- Elevated ISG15 expression was associated with increased CD68+ immune cell infiltration and decreased CD8+ T cell infiltration.
- ISG15 promoted the recruitment of CD68+ cells and inhibited CD8+ T cell chemotaxis in vitro.
Conclusions:
- High ISG15 expression is a characteristic of osteosarcoma, promoting tumorigenesis and metastasis by modulating tumor immunogenicity.
- ISG15 influences the tumor immune microenvironment by recruiting suppressive immune cells and hindering anti-tumor T cell responses.
- ISG15 presents a potential therapeutic target for osteosarcoma treatment.
