Abstract
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein of inflammasomes and a proapoptotic molecule; however, its roles in signal transduction in pancreatic ductal adenocarcinoma (PDAC) cells remain unknown. Here, we clarified the role and mechanisms of action of ASC in PDAC using clinical evidence and in vitro data. ASC expression in PDAC tissues was analyzed using public tumor datasets and immunohistochemistry results of patients who underwent surgery, and PDAC prognosis was investigated using the Kaplan–Meier Plotter. ASC expression in PDAC cells was downregulated using small-interfering RNA, and gene expression was assessed by RNA sequencing. Review of the Oncomine database and immunostaining of surgically removed tissues revealed elevated ASC expression in PDAC tumors relative to non-tumor tissue, indicating poor prognosis. We observed high ASC expression in multiple PDAC cells, with ASC silencing subsequently inhibiting PDAC cell growth and altering the expression of cell cycle-related genes. Specifically, ASC silencing reduced cyclin D1 levels and stopped the cell cycle at the G1 phase but did not modulate the expression of any apoptosis-related molecules. These results show that ASC inhibited tumor progression via cell cycle modulation in PDAC cells and could be a potential therapeutic target.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive disease with the poorest prognosis among human cancers[1]
a caspase recruitment domain (ASC) expression in ducts and acinar cells was weak in tissues distant from the tumor (Fig. 1e); we observed strong expression of ASC in either metaplastic or normal ducts within their nearby normal tissue relative to that in acinar tissue (Fig. 1f), and ASC expression was even stronger in cancerous lesions than surrounding tissues (Fig. 1g)
In recent years, increasing evidence has shown that ASC plays an important role in the interaction between pancreatic ductal adenocarcinoma (PDAC) cells and cells in the surrounding microenvironment[27,28]; the role of ASC in signal transduction in PDAC cells has not been fully investigated
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive disease with the poorest prognosis among human cancers[1]. To explore the clinical significance of ASC in PDAC, we performed Kaplan–Meier analysis, with the results showing that patients with elevated ASC mRNA expression had shorter overall survival (OS; n = 177; HR = 1.79, 95% CI 1.17–2.75) (Fig. 2a). We examined ASC expression in PDAC cell lines, finding increased expression in PANC-1, ASPC-1, and BXPC-3 cells and decreased expression in Mia-PaCa-2 cells relative to that in the pancreatic ductal epithelial cell line hTERT-HPNE, which exhibits an acinar associated with the ductal metaplasia phenotype, according to real-time RT-PCR (Fig. 3a).
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