The Effect And Mechanism Of PSME3 On The Proliferation And Apoptosis Of Pancreatic Cancer Cells And Pancreatic Astrocytes

Pancreatic cancer is a highly malignant disease that is associated with poor prognosis.One hallmark of pancreatie cancer is excessive desmoplasia,characterized by fibrous or cornective tissue growth and altered tumor stroma.Pancreatic stellate cells(PSCs)comprise a mesenchymal cell type that contributes to pancreas fibrosis and cancer progression.PSME3 is a regulatory subunit of the proteasome that is expressed in various cancers such as breast,ovarian,and pancreatic.Notably,PSME3 modulates lactate secretion in pancreatic cancer,suggesting a potential function in regulating pancreas fibrosis.However,the role of PSME3 in pancreatic cancer cell(PCC)-PSC interactions remains unclear.The current study,for the first time,explored the mechanism involved in PSME3-mediated PCC-PSC interactions.IHC showed that PSME3 is highly expressed in PCCs,and this was found to correlate with tumor differentiation.RNA interference(RNAi)indicated that PSME3 is involved in PCC apoptosis.PCR array and cell co-culture experiments suggested that conditioned culture medium(CM)from PSME3-knockdown PCCs could suppress PSC proliferation by down-regulating TGFB1 secretion.Transcription factor(TF)activation assays showed that PSME3 regulates TGFB1 production by inhibiting activation protein-1(AP-1).In vivo,the effect of PSME3 on the tumorigenesis of pancreatic ductal adenocarcinoma cell line was observed in practical nude mice.Dual luciferase reporter assay was used to explore the post-transcriptional regulation of PSME3 in pancreatic cancer cells.Together,these data demonstrate that PSME3 interacts with AP-1 to regulate TGFB1 secretion in PCCs and promote PSC proliferation.PSME3 is one of the post-transcriptional regulatory targets of microRNA-30C-5p in pancreatic cancer cells.Our results indicate a novel PSME3-regulated association between PSCs and PCCs and provide a promising therapeutic strategy for this malignancy.