ESE3-positive PSCs drive pancreatic cancer fibrosis, chemoresistance and poor prognosis via tumour–stromal IL-1β/NF–κB/ESE3 signalling axis

Tiansuo Zhao, Di Xiao, Fanjie Jin, Xugang Sun, Jie Yu, Hongwei Wang, Jing Liu, Wenrun Cai, Chongbiao Huang, Xiuchao Wang, Song Gao, Zhe Liu, Shengyu Yang, Chuntao Gao, Jihui Hao

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background: Desmoplastic stroma, a feature of pancreatic ductal adenocarcinoma (PDAC), contains abundant activated pancreatic stellate cells (PSCs). How PSCs promote PDAC progression remains incompletely understood. Methods: Effect of epithelium-specific E-twenty six factor 3 (ESE3)-positive PSCs on PDAC fibrosis and chemoresistance was examined by western blot, RT-PCR, immunofluorescence, flow cytometry assay, chromatin immunoprecipitation, luciferase assay, immunohistochemistry and subcutaneous pancreatic cancer mouse model. Results: ESE3 expression increased in PSCs in PDAC tissues compared with those in normal PSCs. Clinical data showed that ESE3 upregulation in PSCs was positively correlated with tumour size, pTNM stage, CA19-9, carcinoembryonic antigen and serum CA242 level. ESE3 overexpression in PSCs was an independent negative prognostic factor for disease-free survival and overall survival amongst patients with PDAC. Mechanistically, the conditional medium from the loss and gain of ESE3-expressing PSCs influenced PDAC chemoresistance and tumour growth. ESE3 directly induced the transcription of α-SMA, collagen-I and IL-1β by binding to ESE3-binding sites on their promoters to activate PSCs. IL-1β upregulated ESE3 in PSCs through NF-κB activation, and ESE3 was required for PSC activation by tumour cell-derived IL-1β. Conclusion: Inhibiting the IL-1β/ESE3 (PSCs)/IL-1β-positive feedback loop is a promising therapeutic strategy to reduce tumour fibrosis and increase chemotherapeutic efficacy in PDAC.

Original languageEnglish (US)
Pages (from-to)1461-1472
Number of pages12
JournalBritish Journal of Cancer
Volume127
Issue number8
DOIs
StatePublished - Nov 1 2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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