Tumor-stromal IL1β/ NFκB / ESE3 Signal Axis Drives Pancreatic Cancer Fibrosis, Chemoresistance, Prognosis
Hao, J.; Zhao, T.; Xiao, D.; Jin, F.; Wang, H.; Liu, J.; Cai, W.; Huang, C.; Wang, X.; Gao, S.; Yang, S.
Show abstract
Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis and pancreatic ductal adenocarcinoma (PDAC) progression. The mechanisms controlling PSC activation is not completely understood. Here we investigated the role of ESE3 (Epithelium-Specific ETS factor 3) in PSC activation. We discovered that in PDAC patients ESE3 expression was increased in PSC while decreased in tumor cells. ESE3 overexpression in PSC promoted PSC activation. Condition medium from ESE3-overexprssing PSC promotes PDAC cell migration, chemoresistance, tumor growth and fibrosis. ESE3 directly induced the transcription of -SMA, Collagen 1 and IL-1{beta} by binding to ESE3 binding sites on their promoters to activate PSC. On the other hand, IL-1{beta} upregulates ESE3 in PSC through NF{kappa}B activation and ESE3 is required for PSC activation by tumor cell derived IL-1{beta}. Clinical data showed ESE3 upregulation in PSC was positively correlated with tumor size, pTNM stage, CA19-9, CEA and CA242 level in serum. ESE3 overexpression in PSC was an independent negative prognostic factor for disease-free survival and overall survival among PDAC patients. Inhibition of the IL-1{beta}/ ESE3 (PSC)/ IL-1{beta} positive feedback loop represents a promising therapeutic strategy to reduce tumor fibrosis and increase chemotherapeutic efficacy in PDAC.
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