ISG15 Promotes ERK1 ISGylation, CD8+ T Cell Activation and Suppresses Ovarian Cancer Progression

Yeung, Tsz-Lun; Tsai, Ching Chou; Leung, Cecilia S.; Yeung, C. Au; Thompson, Melissa S.; Lu, Karen H.; Freedman, Ralph S.; Birrer, Michael J.; Wong, Kwong-Kwok; Mok, Samuel C.

doi:10.3390/cancers10120464

Cited by 33 publications

(23 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the extracellular ISG15 acts as an immune adjuvant that promotes antigen-specific CD8 + T cell tumour immunity [ 14 ]. In ovarian cancer, ISG15 can stimulate CD8 + T cell proliferation by activating NK cells, which enhance the cytokines production such as IL2 and IFNγ [ 15 ]. ISG15 is also highly correlated with the expression of the macrophage marker CD68 and it appears to mediate the cellular expression of multiple cytokines in macrophage through the regulation of p38 phosphorylation [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

The prognostic significance of interferon-stimulated gene 15 (ISG15) in invasive breast cancer

Kariri

Alsaleem

Joseph

et al. 2020

Breast Cancer Res Treat

View full text Add to dashboard Cite

Background Lymphovascular invasion (LVI) is a prognostic factor in early-stage invasive breast cancer (BC). Through bioinformatics, data analyses of multiple BC cohorts revealed the positive association between interferon-stimulated gene 15 (ISG15) LVI status. Thus, we explored the prognostic significance of ISG15 in BC. Methods The prognostic significance of ISG15 mRNA was assessed in METABRIC (n = 1980), TCGA (n = 854) and Kaplan–Meier Plotter (n = 3951). ISG15 protein was evaluated using immunohistochemistry (n = 859) in early-stage invasive BC patients with long-term follow-up. The associations between ISG15 expression and clinicopathological features, expression of immune cell markers and patient outcome data were evaluated. Results High mRNA and protein ISG15 expression were associated with LVI, higher histological grade, larger tumour size, hormonal receptor negativity, HER2 positivity, p53 and Ki67. High ISG15 protein expression was associated with HER2-enriched BC subtypes and immune markers (CD8, FOXP3 and CD68). High ISG15 mRNA and ISG15 expressions were associated with poor patient outcome. Cox proportional multivariate analysis revealed that the elevated ISG15 expression was an independent prognostic factor of shorter BC-specific survival. Conclusion This study provides evidence for the role of ISG15 in LVI development and BC prognosis. Further functional studies in BC are warranted to evaluate the therapeutic potential of ISG15.

show abstract

Section: Introductionmentioning

confidence: 99%

The prognostic significance of interferon-stimulated gene 15 (ISG15) in invasive breast cancer

Kariri

Alsaleem

Joseph

et al. 2020

Breast Cancer Res Treat

View full text Add to dashboard Cite

show abstract

“…In our study, recombinant purified ISG15 not only inhibited cell proliferation but more importantly reduced the burden of xenografts in nude mice. In advanced high-grade serous ovarian cancer, recombinant purified ISG15 has also been shown to suppress tumour progression in tumour-bearing animals 36 .…”

Section: Discussionmentioning

confidence: 99%

ISG15 induces ESRP1 to inhibit lung adenocarcinoma progression

Zhang

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

Our previous work demonstrated that Epithelial Splicing Regulatory Protein 1 (ESRP1) could inhibit the progression of lung adenocarcinoma (ADC). When ESRP1 was upregulated, the interferon (IFN) pathway was activated and Interferon-stimulated gene 15 (ISG15) expression increased exponentially in our microarray result. In this study, we aim to explore the function of ISG15 and its interactions with ESRP1 and to provide new insights for ADC treatment. ISG15 expression in lung ADC tissues was determined by immunohistochemistry (IHC) staining. The effect of ISG15 on lung ADC progression was examined by in vitro and in vivo assays. The mechanism of action on ESRP1 regulating ISG15 was investigated using Western blotting, RT-qPCR, immunofluorescence staining, chromatin immunoprecipitation, and a dual luciferase reporter system. The ISGylation between ISG15 and ESRP1 was detected by co-immunoprecipitation. Patients with high ISG15 expression were associated with higher survival rates, especially those with ISG15 expression in the nucleus. In vitro and in vivo experiments showed that upregulation of ISG15 inhibited EMT in lung ADC. ESRP1 upregulated the expression of ISG15 through CREB with enriched ISG15 in the nucleus. Importantly, ISG15 promoted ISGylation of ESRP1 and slowed the degradation of ESRP1, which demonstrated that ESRP1 and ISG15 formed a positive feedback loop and jointly suppressed EMT of lung ADC. In conclusion, ISG15 serves as an independent prognostic marker for long-term survival in lung ADC patients. We have revealed the protective effect of ISG15 against lung ADC progression and the combinatorial benefit of ISG15 and ESRP1 on inhibiting EMT. These findings suggest that reconstituting ISG15 and ESRP1 may have the potential for treating lung ADC.

show abstract

“…Elevated STAT1 increases intra-tumor CD8 + T cells, which plays a significant role in tumor inhibition by direct cytotoxicity ( Wang et al, 2016 ; Jifu et al, 2018 ). Tumor-infiltrating CD8 + T cells suppress OC progression and are associated with a favorable prognosis in OC ( Preston et al, 2013 ; Yeung et al, 2018 ). The Africa American Cancer Epidemiology Study shows that programmed death ligand-1 (PD-L1) positive and IDO positive tumor cells from HGSOC accompany by increased amounts of CD8 + T cells ( Mills et al, 2019 ).…”

Section: Role Of Stat1 In Ovarian Cancermentioning

confidence: 99%

The Dual Role of STAT1 in Ovarian Cancer: Insight Into Molecular Mechanisms and Application Potentials

Wang

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The signal transducer and activator of transcription 1 (STAT1) is a transducer protein and acts as a transcription factor but its role in ovarian cancer (OC) is not completely understood. Practically, there are two-faced effects of STAT1 on tumorigenesis in different kinds of cancers. Existing evidence reveals that STAT1 has both tumor-suppressing and tumor-promoting functions involved in angiogenesis, cell proliferation, migration, invasion, apoptosis, drug resistance, stemness, and immune responses mainly through interacting and regulating target genes at multiple levels. The canonical STAT1 signaling pathway shows that STAT1 is phosphorylated and activated by the receptor-activated kinases such as Janus kinase in response to interferon stimulation. The STAT1 signaling can also be crosstalk with other signaling such as transforming growth factor-β signaling involved in cancer cell behavior. OC is often diagnosed at an advanced stage due to symptomless or atypical symptoms and the lack of effective detection at an early stage. Furthermore, patients with OC often develop chemoresistance and recurrence. This review focuses on the multi-faced role of STAT1 and highlights the molecular mechanisms and biological functions of STAT1 in OC.

show abstract

ISG15 Promotes ERK1 ISGylation, CD8+ T Cell Activation and Suppresses Ovarian Cancer Progression

Cited by 33 publications

References 50 publications

The prognostic significance of interferon-stimulated gene 15 (ISG15) in invasive breast cancer

The prognostic significance of interferon-stimulated gene 15 (ISG15) in invasive breast cancer

ISG15 induces ESRP1 to inhibit lung adenocarcinoma progression

The Dual Role of STAT1 in Ovarian Cancer: Insight Into Molecular Mechanisms and Application Potentials

Contact Info

Product

Resources

About