Abstract
Pancreatic cancer is one of the major malignancies and causes of mortality worldwide. E3 ubiquitin–protein ligases transfer activated ubiquitin from ubiquitin-conjugating enzymes to protein substrates and confer substrate specificity in cancer. In this study, we first downloaded data from The Cancer Genome Atlas pancreatic adenocarcinoma dataset, acquired all 27 differentially expressed genes (DEGs), and identified genomic alterations. Then, the prognostic significance of DEGs was analyzed, and eight DEGs (MECOM, CBLC, MARCHF4, RNF166, TRIM46, LONRF3, RNF39, and RNF223) and two clinical parameters (pathological N stage and T stage) exhibited prognostic significance. RNF223 showed independent significance as an unfavorable prognostic marker and was chosen for subsequent analysis. Next, the function of RNF223 in the pancreatic cancer cell lines ASPC-1 and PANC-1 was investigated, and RNF223 silencing promoted pancreatic cancer growth and migration. To explore the potential targets and pathways of RNF223 in pancreatic cancer, quantitative proteomics was applied to analyze differentially expressed proteins, and metabolism-related pathways were primarily enriched. Finally, the reason for the elevated expression of RNF223 was analyzed, and KLF4 was shown to contribute to the increased expression of RNF233. In conclusion, this study comprehensively analyzed the clinical significance of E3 ligases. Functional assays revealed that RNF223 promotes cancer by regulating cell metabolism. Finally, the elevated expression of RNF223 was attributed to KLF4-mediated transcriptional activation. This study broadens our knowledge regarding E3 ubiquitin ligases and signal transduction and provides novel markers and therapeutic targets in pancreatic cancer.
Highlights
Pancreatic cancer (PC) is one of the major malignancies and causes of mortality worldwide (Cheng et al, 2019; Mizrahi et al, 2020; Siegel et al, 2020)
Diagnosis of PC often occurs at a late stage, meaning that more than 80% of patients with PC are unsuitable for surgical resection (Buscail et al, 2020)
To examine the expression differences in the E3 ligases in PC, 377 genes were applied for statistical analysis
Summary
Pancreatic cancer (PC) is one of the major malignancies and causes of mortality worldwide (Cheng et al, 2019; Mizrahi et al, 2020; Siegel et al, 2020). The most common type of PC is adenocarcinoma, accounting for 95% of cases, which is classified as pancreatic ductal adenocarcinoma (He et al, 2014; Martens et al, 2019). The prognosis for PC remains poor, with only 4.4% of patients reaching a 5-year survival rate (Mizrahi et al, 2020). Risk factors for developing PC include family history, obesity, type 2 diabetes, and tobacco use (Mizrahi et al, 2020). Because of delayed disease detection and the limited efficacy of systemic therapies, the prognosis for this disease remains very poor (Grossberg et al, 2020). Insights regarding the regulatory mechanisms underlying PC progression are required to identify novel diagnostic and/or prognostic markers
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