Immune-Associated Gene Signatures Serve as a Promising Biomarker of Immunotherapeutic Prognosis for Renal Clear Cell Carcinoma

Wang, Qi; Tang, Hao; Luo, Xuehui; Chen, Jie; Zhang, Xinyue; Li, Xinyue; Li, Yuesen; Chen, Yuetong; Xu, Yungang; Han, Suxia

doi:10.3389/fimmu.2022.890150

Cited by 16 publications

(15 citation statements)

References 84 publications

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“…Over 90% of kidney malignancies are RCC, which originates from the renal epithelium 23 . KIRC, a subtype of kidney cancer associated with high death rates, invasion and metastasis, has been found to be insensitive to chemotherapy or radiotherapy 24,25 . Hence, it is crucial to explore alternative molecular indicators to identify and predict the presence and prognosis of KIRC, facilitating the development of a more tailored and effective treatment strategy.…”

Section: Discussionmentioning

confidence: 99%

CPA4 as a biomarker promotes the proliferation, migration and metastasis of clear cell renal cell carcinoma cells

Wang,

Ding,

Liu

et al. 2024

J Cellular Molecular Medi

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Clear cell renal cell carcinoma (ccRCC) is a commonly occurring and highly aggressive urological malignancy characterized by a significant mortality rate. Current therapeutic options for advanced ccRCC are limited, necessitating the discovery of novel biomarkers and therapeutic targets. Carboxypeptidase A4 (CPA4) is a zinc‐containing metallocarboxypeptidase with implications in various cancer types, but its role in ccRCC remains unexplored. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized in order to investigate the differential expression patterns of CPA4. The expression of CPA4 in ccRCC patients was further verified using immunohistochemical (IHC) examination of 24 clinical specimens. A network of protein–protein interactions (PPI) was established, incorporating CPA4 and its genes that were expressed differentially. Functional enrichment analyses were conducted to anticipate the contribution of CPA4 in the development of ccRCC. To validate our earlier study, we conducted real‐time PCR and cell functional tests on ccRCC cell lines. Our findings revealed that CPA4 is overexpressed in ccRCC, and the higher the expression of CPA4, the worse the clinical outcomes such as TNM stage, pathological stage, histological grade, etc. Moreover, patients with high CPA4 expression had worse overall survival, disease‐specific survival and progress‐free interval than patients with low expression. The PPI network analysis highlighted potential interactions contributing to ccRCC progression. Functional enrichment analysis indicated the involvement of CPA4 in the regulation of key pathways associated with ccRCC development. Additionally, immune infiltration analysis suggested a potential link between CPA4 expression and immune response in the tumour microenvironment. Finally, cell functional studies in ccRCC cell lines shed light on the molecular mechanisms underlying the role of CPA4 in promoting ccRCC formation. Overall, our study unveils CPA4 as a promising biomarker with prognostic potential in ccRCC. The identified interactions and pathways provide valuable insights into its implications in ccRCC development and offer a foundation for future research on targeted therapies. Further investigation of CPA4's involvement in immune responses may contribute to the development of immunotherapeutic strategies for ccRCC treatment.

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Section: Discussionmentioning

confidence: 99%

CPA4 as a biomarker promotes the proliferation, migration and metastasis of clear cell renal cell carcinoma cells

Wang,

Ding,

Liu

et al. 2024

J Cellular Molecular Medi

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“…The AUC values of 1-year, 2-year, and 3-year PFS were 0.940 (95% CI: 0.894–0.985), 0.981 (95% CI: 0.960–1.000), and 0.969 (95% CI: 0.937–1.000), respectively. Although numerous researchers have developed many biomarkers to predict the survival time of patients with ccRCC, they have not been able to predict the survival time of patients receiving immunotherapy because the patients included did not receive anti-PD-1 treatment [ 55 , 56 , 57 ]. There are also quite a few biomarkers that can predict the responsiveness of ccRCC to anti-PD-1, for example, a novel signature composed of 47 genes can predict the response to anti-PD-1 therapy, and the AUC value is as high as 0.93 [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

A New Signature That Predicts Progression-Free Survival of Clear Cell Renal Cell Carcinoma with Anti-PD-1 Therapy

Lin

Cai

et al. 2023

IJMS

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Immunotherapy has greatly improved the survival time and quality of life of patients with renal cell carcinoma, but the benefits are limited to a small portion of patients. There are too few new biomarkers that can be used to identify molecular subtypes of renal clear cell carcinoma and predict survival time with anti-PD-1 treatment. Single-cell RNA data of clear cell renal cell carcinoma (ccRCC) treated with anti-PD-1 were obtained from public databases, then 27,707 high-quality CD4 + T and CD8 + T cells were obtained for subsequent analysis. Firstly, genes set variation analysis and CellChat algorithm were used to explore potential molecular pathway differences and intercellular communication between the responder and non-responder groups. Additionally, differentially expressed genes (DEGs) between the responder and non-responder groups were obtained using the “edgeR” package, and ccRCC samples from TCGA-KIRC (n = 533) and ICGA-KIRC (n = 91) were analyzed by the unsupervised clustering algorithm to recognize molecular subtypes with different immune characteristics. Finally, using univariate Cox analysis, least absolute shrinkage and selection operator (Lasso) regression, and multivariate Cox regression, the prognosis model of immunotherapy was established and verified to predict the progression-free survival of ccRCC patients treated with anti-PD-1. At the single cell level, there are different signal pathways and cell communication between the immunotherapy responder and non-responder groups. In addition, our research also confirms that the expression level of PDCD1/PD-1 is not an effective marker for predicting the response to immune checkpoint inhibitors (ICIs). The new prognostic immune signature (PIS) enabled the classification of ccRCC patients with anti-PD-1 therapy into high- and low-risk groups, and the progression-free survival times (PFS) and immunotherapy responses were significantly different between these two groups. In the training group, the area under the ROC curve (AUC) for predicting 1-, 2- and 3-year progression-free survival was 0.940 (95% CI: 0.894–0.985), 0.981 (95% CI: 0.960–1.000), and 0.969 (95% CI: 0.937–1.000), respectively. Validation sets confirm the robustness of the signature. This study revealed the heterogeneity between the anti-PD-1 responder and non-responder groups from different angles and established a robust PIS to predict the progression-free survival of ccRCC patients receiving immune checkpoint inhibitors.

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“…Patients with ccRCC often develop advanced stages and high-grade status at the rst diagnosis and miss the opportunity for surgery [30]. Due to its insensitivity to radiotherapy and chemotherapy, patients with ccRCC are often accompanied with a poor prognosis [31]. Although immunotherapy and molecular targeted therapy have been used as rst-line therapies for ccRCC, drug resistance and low Overall Response Rate (ORR) to immunotherapy still limit their further application [4,32].…”

Section: Discussionmentioning

confidence: 99%

NEIL3 promotes the proliferation of ccRCC via the cyclin D1-Rb-E2F1 feedback loop regulation

Zhang

Wang

Yue

et al. 2023

Preprint

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Backgrounds: Nei endonuclease VIII-like 3 (NEIL3), a novel tumor-related gene, was differentially expressed and involved in pathophysiological processes in multiple tumors. However, the potential biological functions and molecular mechanisms of NEIL3 in human clear cell renal cell carcinoma (ccRCC) have not been identified.Methods The expression pattern and prognostic value of NEIL3 in ccRCC patients were analyzed in multiple comprehensive databases and validated by qRT-PCR, western blotting analysis, immunohistochemistry, and tissue chips. The regulatory mechanisms were verified by the GSEA analysis, chromatin immunoprecipitation, dual-luciferase reporter gene, and immunofluorescence assay. The oncogenic effect of NEIL3 in ccRCC was confirmed by MTT assay, colony formation assay, tumorsphere assay, cell flow cytometry analysis, and xenograft tumor models.Results Nei endonuclease VIII-like 3 (NEIL3), a novel tumor-related gene, was highly expressed in ccRCC and positively correlated with adverse clinicopathological characteristics and worse prognosis. Mechanistically, we demonstrated that NEIL3 promoted cell proliferation and cell cycle progression in vitro and tumor growth in vivo. Furthermore, we found that NEIL3 overexpression activated the cyclin D1-Rb-E2F1 pathway. The E2F1 elevation then promoted the proliferation, cell cycle transition, and the NEIL3 expression, thus forming a feedback loop of the NEIL3-E2F1 axis to contribute to ccRCC progression. In addition, there was a positive correlation between NEIL3 and E2F1 expression in clinical specimens of ccRCC.Conclusion NEIL3 and cyclin D1-Rb-E2F1 pathway form a positive feedback loop and coordinately contribute to ccRCC progression. NEIL3 presents as a novel candidate for ccRCC diagnosis and treatment.

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Immune-Associated Gene Signatures Serve as a Promising Biomarker of Immunotherapeutic Prognosis for Renal Clear Cell Carcinoma

Cited by 16 publications

References 84 publications

CPA4 as a biomarker promotes the proliferation, migration and metastasis of clear cell renal cell carcinoma cells

CPA4 as a biomarker promotes the proliferation, migration and metastasis of clear cell renal cell carcinoma cells

A New Signature That Predicts Progression-Free Survival of Clear Cell Renal Cell Carcinoma with Anti-PD-1 Therapy

NEIL3 promotes the proliferation of ccRCC via the cyclin D1-Rb-E2F1 feedback loop regulation

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