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Pancreas
Original research
ESE3/EHF, a promising target of rosiglitazone, suppresses pancreatic cancer stemness by downregulating CXCR4
  1. Tianxing Zhou1,
  2. Jing Liu1,2,
  3. Yongjie Xie1,
  4. Shuai Yuan1,
  5. Yu Guo3,
  6. Weiwei Bai1,
  7. Kaili Zhao1,
  8. Wenna Jiang1,
  9. Hongwei Wang1,
  10. Haotian Wang1,
  11. Tiansuo Zhao1,
  12. Chongbiao Huang1,
  13. Song Gao1,
  14. Xiuchao Wang1,
  15. Shengyu Yang4,
  16. Jihui Hao1
  1. 1 Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China
  2. 2 Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
  3. 3 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
  4. 4 Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA
  1. Correspondence to Professor Jihui Hao, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, PR China; haojihui{at}tjmuch.com

Abstract

Background and aims The crosstalk between cancer stem cells (CSCs) and their niche is required for the maintenance of stem cell-like phenotypes of CSCs. Here, we identified E26 transformation-specific homologous factor (EHF) as a key molecule in decreasing the sensitivity of pancreatic cancer (PC) cells to CSCs’ niche stimulus. We also explored a therapeutic strategy to restore the expression of EHF.

Design We used a LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse model and samples from patients with PC. Immunostaining, flow cytometry, sphere formation assays, anchorage-independent growth assay, in vivo tumourigenicity, reverse transcription PCR, chromatin immunoprecipitation (ChIP) and luciferase analyses were conducted in this study.

Results CXCL12 derived from pancreatic stellate cells (PSCs) mediates the crosstalk between PC cells and PSCs to promote PC stemness. Tumorous EHF suppressed CSC stemness by decreasing the sensitivity of PC to CXCL12 stimulus and inhibiting the crosstalk between PC and CSC-supportive niches. Mechanically, EHF suppressed the transcription of the CXCL12 receptor CXCR4. EHF had a cell autonomous role in suppressing cancer stemness by inhibiting the transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppressed PC stemness and inhibited the crosstalk between PC and PSCs by upregulating EHF. Preclinical KPC mouse cohorts demonstrated that rosiglitazone sensitised PDAC to gemcitabine therapy.

Conclusions EHF decreased the sensitivity of PC to the stimulus from PSC-derived CSC-supportive niche by negatively regulating tumorous CXCR4. Rosiglitazone could be used to target PC stem cells and the crosstalk between CSCs and their niche by upregulating EHF.

  • pancreatic cancer
  • stem cells

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/gutjnl-2020-321952

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • TZ, JL and YX contributed equally.

    • Contributors JH and JL conceived and designed the experiments; TZ and YX performed most of the experiments; JL, WB, KZ, WJ, SY, HoWang and HaWang performed some experiments; YG, CH and SY provided technical support; TZ, SG, XW provided patient samples and technical support. JH, JL, TZ and YX analysed and discussed the data. JL and TZ wrote and completed the paper. JH supervised the entire project.

    • Funding This work was supported by the National Natural Science Foundation of China (grants 82030092, 81720108028, 82072657, 81802432, 82072716, 81802433, 82072659, 81871968 and 81871978), the programmes of Tianjin Prominent Talents, Tianjin Eminent Scholars, Tianjin Natural Science Fundation (20JCQNJC01330, 18JCJQJC47800, 19JCJQJC63100 and 19JCYBJC26200), Tianjin Postgraduate Research and Innovation Project (2019YJSB104), and Tianjin Research Innovation Project for Postgraduate Students (2019YJSB104). The research in S. Yang’s laboratory is supported by the National Cancer Institute (R01 CA175741) and the Elsa U. Pardee Foundation (R01 CA175741)

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.