PSME3 promotes TGFB1 secretion by pancreatic cancer cells to induce pancreatic stellate cell proliferation

Abstract

Pancreatic cancer is a highly malignant disease that is associated with poor prognosis. One hallmark of pancreatic cancer is excessive desmoplasia, characterized by fibrous or connective 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). Together, these data demonstrate that PSME3 interacts with AP-1 to regulate TGFB1 secretion in PCCs and promote PSC proliferation. Our results indicate a novel PSME3-regulated association between PSCs and PCCs and provide a promising therapeutic strategy for this malignancy.