RESUMEN
Despite significant advances in diagnostic techniques and treatment approaches, the prognosis of pancreatic ductal adenocarcinoma (PDAC) is still poor. Previous studies have reported that S-phase kinase-associated protein 2 (SKP2), a subunit of the SCF E3 ubiquitin ligase complex, is engaged in the malignant biological behavior of some tumor entities. However, SKP2 has not been fully investigated in PDAC. In the present study, it was observed that high expression of SKP2 significantly correlates with decreased survival time. Further experiments suggested that SKP2 promotes metastasis by interacting with the putative transcription factor paraspeckle component 1 (PSPC1). According to the results of coimmunoprecipitation and ubiquitination assays, SKP2 depletion resulted in the polyubiquitination of PSPC1, followed by its degradation. Furthermore, the SKP2-mediated ubiquitination of PSPC1 partially depended on the activity of the E3 ligase TRIM21. In addition, inhibition of the SKP2/PSPC1 axis by SMIP004, a traditional inhibitor of SKP2, impaired the migration of PDAC cells. In summary, this study provides novel insight into the mechanisms involved in PDAC malignant progression. Targeting the SKP2/PSPC1 axis is a promising strategy for the treatment of PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Proteínas Quinasas Asociadas a Fase-S/genética , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Neoplasias Pancreáticas/genética , Ubiquitinación , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Carcinoma Ductal Pancreático/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
BACKGROUND: Previous studies have described that the SEC23A gene is involved in the occurrence and development of various tumor entities. However, little is known about its expression and relevance in stomach adenocarcinoma (STAD). The aim of this study was to bioinformatically analyze the role of SEC23A in STAD, followed by patient tissue sample analyses. MATERIALS AND METHODS: SEC23A expression levels in STAD and normal gastric tissues were analyzed in the Cancer Genome Atlas and Gene Expression Omnibus databases; results were verified in fresh clinical STAD specimens on both gene and protein expression levels. SEC23A expression correlated with survival parameters by Kaplan-Meier and multivariate Cox regression analyses. The top genes co-expressed with SEC23A were identified by gene set enrichment analysis (GSEA) using the clusterProfiler package in R. Furthermore, the R package (immunedeconv), integrating the CIBERSORT algorithm, was used to estimate immune cell infiltration levels in STAD. RESULTS: SEC23A gene and sec23a protein expression were both significantly upregulated in STAD, and this correlated with the pT stage. Moreover, high SEC23A expression was associated with poor disease-free and overall survival of STAD patients. Cox analyses revealed that besides age and pathologic stage, SEC23A expression is an independent risk factor for STAD. GSEA indicated that SEC23A was positively associated with ECM-related pathways. In the CIBERSORT analysis, the level of SEC23A negatively correlated with various infiltrating immune cell subsets, including follicular helper T cells, Tregs, activated NK cells and myeloid dendritic cells. Finally, the expression levels of immune checkpoint-related genes, including HAVCR2 and PDCD1LG2, were significantly increased in the high SEC23A expression group. CONCLUSIONS: We observed the significantly upregulated expression of SEC23A in STAD, an association with disease progression, patients' prognosis and infiltrating immune cell subsets. Thus, we propose SEC23A as an independent prognostic factor with a putative role in immune response regulation in STAD.
