Identification of ISG15 and ZFP36 as novel hypoxia- and immune-related gene signatures contributing to a new perspective for the treatment of prostate cancer by bioinformatics and experimental verification

Li, Yunxue

doi:10.1186/s12967-022-03398-4

Cited by 17 publications

(9 citation statements)

References 53 publications

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“…Several studies have shown that patients with higher immune scores and lower stromal scores have a better prognosis ( 49 , 50 ). However, the low-CRIRS group with a better prognosis had higher stromal scores and lower immune scores, and no significant differences in immune microenvironment scores were observed between the low and high CRIRS groups in our study ( Figures 9A–C ).…”

Section: Resultsmentioning

confidence: 99%

The signature of cuproptosis-related immune genes predicts the tumor microenvironment and prognosis of prostate adenocarcinoma

Yao

Zhang

et al. 2023

Front. Immunol.

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BackgroundCuproptosis plays a crucial role in cancer, and different subtypes of cuproptosis have different immune profiles in prostate adenocarcinoma (PRAD). This study aimed to investigate immune genes associated with cuproptosis and develop a risk model to predict prognostic characteristics and chemotherapy/immunotherapy responses of patients with PRAD.MethodsThe CIBERSORT algorithm was used to evaluate the immune and stromal scores of patients with PRAD in The Cancer Genome Atlas (TCGA) cohort. Validation of differentially expressed genes DLAT and DLD in benign and malignant tissues by immunohistochemistry, and the immune-related genes of DLAT and DLD were further screened. Univariable Cox regression were performed to select key genes. Least absolute shrinkage and selection operator (LASSO)–Cox regression analyse was used to develop a risk model based on the selected genes. The model was validated in the TCGA, Memorial Sloan-Kettering Cancer Center (MSKCC) and Gene Expression Omnibus (GEO) datasets, as well as in this study unit cohort. The genes were examined via functional enrichment analysis, and the tumor immune features, tumor mutation features and copy number variations (CNVs) of patients with different risk scores were analysed. The response of patients to multiple chemotherapeutic/targeted drugs was assessed using the pRRophetic algorithm, and immunotherapy was inferred by the Tumor Immune Dysfunction and Exclusion (TIDE) and immunophenoscore (IPS).ResultsCuproptosis-related immune risk scores (CRIRSs) were developed based on PRLR, DES and LECT2. High CRIRSs indicated poor overall survival (OS), disease-free survival (DFS) in the TCGA-PRAD, MSKCC and GEO datasets and higher T stage and Gleason scores in TCGA-PRAD. Similarly, in the sample collected by the study unit, patients with high CRIRS had higher T-stage and Gleason scores. Additionally, higher CRIRSs were negatively correlated with the abundance of activated B cells, activated CD8+ T cells and other stromal or immune cells. The expression of some immune checkpoints was negatively correlated with CRIRSs. Tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH) and copy number variation (CNV) scores were all higher in the high-CRIRS group. Multiple chemotherapeutic/targeted drugs and immunotherapy had better responsiveness in the low-CRIRS group.ConclusionOverall, lower CRIRS indicated better response to treatment strategies and better prognostic outcomes.

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Section: Resultsmentioning

confidence: 99%

The signature of cuproptosis-related immune genes predicts the tumor microenvironment and prognosis of prostate adenocarcinoma

Yao

Zhang

et al. 2023

Front. Immunol.

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“…Indeed, a recent meta-analysis study identified miR-21 as one of several miRNAs that could predict responses to androgen-deprivation therapy [95]. Elsewhere, various research groups have developed hypoxic signature panels of gene markers to predict prostate cancer prognoses and treatment outcomes, although notably these did not include microRNAs [96][97][98][99]. Our research suggests that hypoxia-induced miRNAs should really be included in such panels, especially if blood-based markers are preferred.…”

Section: Discussionmentioning

confidence: 97%

MiR-21 Is Induced by Hypoxia and Down-Regulates RHOB in Prostate Cancer

Angel

Stafford

McNally

et al. 2023

Cancers

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Tumour hypoxia is a well-established contributor to prostate cancer progression and is also known to alter the expression of several microRNAs. The over-expression of microRNA-21 (miR-21) has been consistently linked with many cancers, but its role in the hypoxic prostate tumour environment has not been well studied. In this paper, the link between hypoxia and miR-21 in prostate cancer is investigated. A bioinformatic analysis of The Cancer Genome Atlas (TCGA) prostate biopsy datasets shows the up-regulation of miR-21 is significantly associated with prostate cancer and clinical markers of disease progression. This up-regulation of miR-21 expression was shown to be caused by hypoxia in the LNCaP prostate cancer cell line in vitro and in an in vivo prostate tumour xenograft model. A functional enrichment analysis also revealed a significant association of miR-21 and its target genes with processes related to cellular hypoxia. The over-expression of miR-21 increased the migration and colony-forming ability of RWPE-1 normal prostate cells. In vitro and in silico analyses demonstrated that miR-21 down-regulates the tumour suppressor gene Ras Homolog Family Member B (RHOB) in prostate cancer. Further a TCGA analysis illustrated that miR-21 can distinguish between different patient outcomes following therapy. This study presents evidence that hypoxia is a key contributor to the over-expression of miR-21 in prostate tumours, which can subsequently promote prostate cancer progression by suppressing RHOB expression. We propose that miR-21 has good potential as a clinically useful diagnostic and prognostic biomarker of hypoxia and prostate cancer.

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“…ISG15 was the first ubiquitin-like protein (Ubl) to be identified and acts not only in the unconjugated/conjugated form inside the cell, but also in the free form outside the cell [ 10 , 21 ]. ISG15 and the enzymes that catalyze ISGylation and de-ISGylation are dysregulated in many types of cancer, including breast, pancreatic, and prostate cancers [ 14 , 22 – 24 ]. However, it remains uncertain whether ISG15 and ISGylation play a pro-tumor or anti-tumor role in cancer.…”

Section: Discussionmentioning

confidence: 99%

ISG15 targets glycosylated PD-L1 and promotes its degradation to enhance antitumor immune effects in lung adenocarcinoma

Zhang

Yan

et al. 2023

J Transl Med

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Background Immunocheckpoint inhibitors (ICIs) have been widely used in the clinical treatment of lung cancer. Although clinical studies and trials have shown that patients can benefit significantly after PD-1/PD-L1 blocking therapy, less than 20% of patients can benefit from ICIs therapy due to tumor heterogeneity and the complexity of immune microenvironment. Several recent studies have explored the immunosuppression of PD-L1 expression and activity by post-translational regulation. Our published articles demonstrate that ISG15 inhibits lung adenocarcinoma progression. Whether ISG15 can enhance the efficacy of ICIs by modulating PD-L1 remains unknown. Methods The relationship between ISG15 and lymphocyte infiltration was identified by IHC. The effects of ISG15 on tumor cells and T lymphocytes were assessed using RT-qPCR and Western Blot and in vivo experiments. The underlying mechanism of PD-L1 post-translational modification by ISG15 was revealed by Western blot, RT-qPCR, flow cytometry, and Co-IP. Finally, we performed validation in C57 mice as well as in lung adenocarcinoma tissues. Results ISG15 promotes the infiltration of CD4+ T lymphocytes. In vivo and in vitro experiments demonstrated that ISG15 induces CD4+ T cell proliferation and invalidity and immune responses against tumors. Mechanistically, we demonstrated that the ubiquitination-like modifying effect of ISG15 on PD-L1 increased the modification of K48-linked ubiquitin chains thus increasing the degradation rate of glycosylated PD-L1 targeting proteasomal pathway. The expression of ISG15 and PD-L1 was negatively correlated in NSCLC tissues. In addition, reduced accumulation of PD-L1 by ISG15 in mice also increased splenic lymphocyte infiltration as well as promoted cytotoxic T cell infiltration in the tumor microenvironment, thereby enhancing anti-tumor immunity. Conclusions The ubiquitination modification of PD-L1 by ISG15 increases K48-linked ubiquitin chain modification, thereby increasing the degradation rate of glycosylated PD-L1-targeted proteasome pathway. More importantly, ISG15 enhanced the sensitivity to immunosuppressive therapy. Our study shows that ISG15, as a post-translational modifier of PD-L1, reduces the stability of PD-L1 and may be a potential therapeutic target for cancer immunotherapy.

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Identification of ISG15 and ZFP36 as novel hypoxia- and immune-related gene signatures contributing to a new perspective for the treatment of prostate cancer by bioinformatics and experimental verification

Cited by 17 publications

References 53 publications

The signature of cuproptosis-related immune genes predicts the tumor microenvironment and prognosis of prostate adenocarcinoma

The signature of cuproptosis-related immune genes predicts the tumor microenvironment and prognosis of prostate adenocarcinoma

MiR-21 Is Induced by Hypoxia and Down-Regulates RHOB in Prostate Cancer

ISG15 targets glycosylated PD-L1 and promotes its degradation to enhance antitumor immune effects in lung adenocarcinoma

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