ABSTRACT
NLRP3 inflammasome activation plays an important role in the development of pancreatic fibrosis. However, it is unclear whether the activation of the NLRP3 inflammasome is directly involved in the activation of Pancreatic stellate cells (PSCs). The aim of this study was to investigate the role and mechanism of the NLRP3 inflammasome in the activation of PSCs. In vivo, a rat model of chronic pancreatitis (CP) was induced by intravenous injection of dibutyltin dichloride (DBTC). In vitro, rat primary PSCs were isolated from pancreatic tissues and incubated with the NLRP3 inflammasome activator LPS, the NLRP3 inhibitor MCC950, or NLRP3 siRNA. The results showed that the expression of NLRP3, pro-Caspase-1, Caspase-1 and IL-18 was increased in the rat model of CP and during PSCs activation. LPS increased the protein levels of NLRP3, ASC, Caspase-1, IL-1ß and IL-18 accompanied by the upregulation of α-SMA, Col I and FN expression. Moreover, MCC950 or NLPR3 siRNA decreased the expression of α-SMA, Col I, FN, TGF-ß1 and p-Smad3. Furthermore, MCC950 reversed the LPS-induced upregulation of α-SMA, FN and Col â expression in PSCs. This study revealed that the NLRP3 inflammasome is directly involved in the activation of PSCs in vivo and in vitro. Inhibiting NLRP3 suppresses the activation of PSCs through the TGF-ß1/Smad3 pathway.
Subject(s)
Fibrosis/metabolism , Inflammasomes/metabolism , Lipopolysaccharides/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pancreatic Stellate Cells/metabolism , Animals , Caspase 1/metabolism , Cells, Cultured , Fibrosis/chemically induced , Rats, Wistar , Transforming Growth Factor beta1/metabolismABSTRACT
Gallbladder cancer (GBC) is a malignant tumor of the biliary tract. The main problem affecting the treatment of gallbladder cancer is late diagnosis and poor prognosis. EIF5A2 is one of two isoforms of the EIF5A family and is reported to be a new oncogenic protein in many human cancers. In this study, our results showed for the first time that EIF5A2 was overexpressed in GBC samples compared with non-tumor tissue. Overexpression of EIF5A2 was associated with lymph node metastasis, tumor differentiation, UICC (Union for International Cancer Control) staging, histological type, metastasis, and tumor size. Overexpression of EIF5A2 in gallbladder carcinoma tissues is also associated with poor prognosis in patients. The interference of EIF5A2 significantly inhibited the proliferation, cell cycle, migration and colony formation of GBC-SD cells in vitro. Our results suggest that EIF5A2 is a target oncogene and may be an important prognostic biomarker in the pathogenesis of gallbladder cancer.
