RESUMO
Although renal cell carcinoma (RCC) is a prevalent type of cancer, the most common pathological subtype, clear cell renal cell carcinoma (ccRCC), still has poorly understood molecular mechanisms of progression. Moreover, interferon-stimulated gene 15 (ISG15) is associated with various types of cancer; however, its biological role in ccRCC remains unclear.This study aimed to explore the role of ISG15 in ccRCC progression.ISG15 expression was upregulated in ccRCC and associated with poor prognosis. RNA sequence analysis and subsequent experiments indicated that ISG15 modulated IL6/JAK2/STAT3 signaling to promote ccRCC proliferation, migration, and invasion. Additionally, our animal experiments confirmed that sustained ISG15 knockdown reduced tumor growth rate in nude mice and promoted cell apoptosis. ISG15 modulates the IL6/JAK2/STAT3 pathway, making it a potential therapeutic target and prognostic biomarker for ccRCC.
Assuntos
Carcinoma de Células Renais , Proliferação de Células , Citocinas , Interleucina-6 , Janus Quinase 2 , Neoplasias Renais , Camundongos Nus , Fator de Transcrição STAT3 , Transdução de Sinais , Ubiquitinas , Humanos , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/genética , Animais , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Janus Quinase 2/metabolismo , Interleucina-6/metabolismo , Interleucina-6/genética , Citocinas/metabolismo , Ubiquitinas/metabolismo , Ubiquitinas/genética , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/genética , Camundongos , Linhagem Celular Tumoral , Masculino , Movimento Celular , Feminino , Apoptose , Regulação Neoplásica da Expressão Gênica , Prognóstico , Progressão da DoençaRESUMO
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma. P4HA3 is a key enzyme in collagen biosynthesis and has emerged as important molecules in regulation of proliferation, invasion, and metastasis in various tumor types. The role of P4HA3 in the development of ccRCC has remained to be elucidated. Genes expression, prognostic, and enrichment analyses were carried out with bioinformatics analysis. The efficiency of P4HA3 knockdown was confirmed by real-time quantitative PCR and Western blotting. The cellular functions were analyzed by CCK-8, EdU, wound healing, and transwell assays. The levels of related proteins expression were analyzed by Western blotting. P4HA3 was highly expressed in ccRCC compared with normal tissue samples from the TCGA database. Kaplan-Meier curves results showed that the expression level of P4HA3 was significantly negatively correlated with overall survival of patients. P4HA3 expression knockdown inhibited the proliferation, migration, and invasion of ccRCC cells, as demonstrated by in vitro experiments. In addition, GSEA results revealed that P4HA3 may be related to EMT and involved in the PI3K-AKT-GSK3ß pathway in ccRCC; this was tentatively confirmed through Western blotting. P4HA3 may induce ccRCC progression via the PI3K-AKT-GSK3ß signaling pathway and could represent a potential therapeutic target.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Pró-Colágeno-Prolina Dioxigenase , Humanos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Glicogênio Sintase Quinase 3 beta/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Heat shock proteins (HSPs) are widely involved in tumor occurrence and development and are prognostic markers for multiple tumors. However, the role of HSPs in clear cell renal cell carcinoma (ccRCC) remains unclear. METHODS: We used Cytoscape to identify hub genes in the ccRCC single-cell sequencing data set from the Gene Expression Omnibus (GEO) data repository. We identified subtypes, C1 and C2, of The Cancer Genome Atlas (TCGA) patients based on the expression of hub genes using unsupervised consensus clustering. Principal component analysis (PCA) was used to verify the clustering differences, and Kaplan-Meier (K-M) estimate was used to verify the survival differences between C1 and C2 patients. We used TIMER 2.0 and CIBERSORT to evaluate the immune cell infiltration of HSP genes and C1 and C2 patients. The R package "pRRophetic" was used to evaluate the sensitivity in C1 and C2 patients to the four first-line treatment drugs. RESULTS: We identified six hub genes (HSP90AA1, HSPH1, HSPA1B, HSPA8, and HSPA1A) encoding HSP, five of which were significantly downregulated in TCGA group, and four had a protective effect on prognosis (p <0.05). Survival analysis showed that C1 patients had a better overall survival (p <0.001). TIMER 2.0 analysis showed that three HSP genes were significantly correlated with the infiltration of CD4+ T cells and CD4+ Th1 cells (|cor|>0.5, p<0.001). CIBERSORT showed significant differences in multiple infiltrating immune cells between C1 and C2 patients. Meanwhile, the expression of PD1 was significantly lower in C1 patients than in C2 patients, and the expression of PDL1 is the another way around. Drug sensitivity analysis showed that C1 patients were more sensitive to sorafenib, pazopanib, and axitinib (p <0.001). CONCLUSION: Our research revealed two molecular subtypes of ccRCC based on 6 HSP genes, and revealed significant differences between the two subtypes in terms of clinical prognosis, immune infiltration, and drug sensitivity.
