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Ubiquitin specific peptidase 19 is a prognostic biomarker and affect the proliferation and migration of clear cell renal cell carcinoma.

ABSTRACT: Ubiquitin specific peptidase 19 (USP19) is a member of the USP family and exhibits diverse roles in various biological processes, such as cell differentiation, cell cycle progression and apoptosis. There is limited knowledge regarding the role and impact of USP19 in cancer, particularly clear cell renal cell carcinoma (ccRCC). To examine the function of USP19 in ccRCC, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases were examined to determine USP19 mRNA expression levels. USP19 mRNA levels were significantly lower in ccRCC tissues than in normal tissues. USP19 downregulation was associated with ccRCC progression and poor prognostic outcomes in TCGA cohort. Furthermore, the functional involvement of USP19 in ccRCC was examined using Cell Counting Kit?8, soft agar, Transwell and wound healing assays in vitro following overexpression or knockdown of USP19 in the Caki?1 cell line. USP19 overexpression inhibited ccRCC proliferation and migration, whereas USP19 knockdown promoted ccRCC proliferation and migration in vitro. Consistent with these results, it was further demonstrated that USP19 downregulation promoted tumor growth in vivo in a xenograft model. Mechanistically, it was found that USP19 exerted its inhibitory effect on ccRCC proliferation and migration by suppressing the activation of ERK. Collectively, the present findings identified a role for USP19 as a tumor suppressor in ccRCC and demonstrated that USP19 is a potential prognostic biomarker that could be applied in ccRCC therapy.

SUBMITTER: Hu W

PROVIDER: S-EPMC7160536 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Ubiquitin specific peptidase 19 is a prognostic biomarker and affect the proliferation and migration of clear cell renal cell carcinoma.

Hu Wenbing W Su Yanfang Y Fei Xinxiong X Wang Xudong X Zhang Guanglin G Su Chunyan C Du Tianxing T Yang Tao T Wang Gangsheng G Tang Ze Z Zhang Jierong J

Oncology reports 20200326 6

Ubiquitin specific peptidase 19 (USP19) is a member of the USP family and exhibits diverse roles in various biological processes, such as cell differentiation, cell cycle progression and apoptosis. There is limited knowledge regarding the role and impact of USP19 in cancer, particularly clear cell renal cell carcinoma (ccRCC). To examine the function of USP19 in ccRCC, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases were examined to determine USP19 mRNA expression levels. US ...[more]

PMID: 32236633

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Project description: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.

Project description:The tumor microenvironment (TME) plays an important part in the initiation and development of clear cell renal cell carcinoma (ccRCC). However, an understanding of the immune infiltration in TME is still unknown. Our study aims to explore the correlation between the TME and the clinical features, as well as the prognosis of ccRCC. In the present study, ESTIMATE and CIBERSORT computational methods were applied to calculate the proportion of tumor-infiltrating immune cells (TICs) and the amount of immune and stromal fractions in the ccRCC form The Cancer Genome Atlas (TCGA) database. Then, we sought to find out those immune cell types and genes which may play a significant role and validated them in the GEO database. Furthermore, an immunohistochemical analysis of our external validation dataset was used to detect SAA1 and PDL1 expression in the ccRCC cancer tissues and corresponding normal tissues. Statistical analysis was performed to study the relationship between SAA1 and clinical characteristics, as well as PDL1 expression. Furthermore, a ccRCC cell model with SAA1 knockdown was constructed, which was used for cell proliferation and the migration test. The intersection analysis of the univariate COX and PPI analysis were performed to imply Serum Amyloid A1 (SAA1) as a predictive factor. The expression of SAA1 was significantly negatively correlated to OS and positively correlated to the clinical TMN stage system. The genes in the high-expression SAA1 group were basically enriched in immune-related activities. The proportion of mast cells resting was negatively correlated with SAA1 expression, indicating that SAA1 may be involved in the maintenance of the immune status for the TME. Moreover, the PDL1 expression was positively related to the SAA1 expression and negatively correlated with the patients' prognosis. Further experiments revealed that the knockdown of SAA1 inhibited ccRCC development through suppressing cell proliferation and migration. SAA1 may be a novel marker for the prognosis prediction of ccRCC patients and may play a vital role in the TME by mast cell resting and PDL1 expression. SAA1 has the potential to become a therapeutic target and indicator for immune target therapy in ccRCC treatment.

Dataset Information

Ubiquitin specific peptidase 19 is a prognostic biomarker and affect the proliferation and migration of clear cell renal cell carcinoma.

Publications

Ubiquitin specific peptidase 19 is a prognostic biomarker and affect the proliferation and migration of clear cell renal cell carcinoma.

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