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ELF3 suppresses gallbladder cancer development through downregulation of the EREG/EGFR/mTOR complex 1 signalling
Takeharu Nakamura1, Yoshihiro Nishikawa1,2, Masahiro Shiokawa1
1Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Abstract:
The prognosis of gallbladder cancer (GBC) remains poor, and a better understanding of GBC molecular mechanisms is important. Genome sequencing of human GBC has demonstrated that loss-of-function mutations of E74-like ETS transcription factor 3 (ELF3) are frequently observed, with ELF3 considered to be a tumour suppressor in GBC. To clarify the underlying molecular mechanisms by which ELF3 suppresses GBC development, we performed in vivo analysis using a combination of autochthonous and allograft mouse models. We first evaluated the clinical significance of ELF3 expression in human GBC tissues and found that low ELF3 expression was associated with advanced clinical stage and deep tumour invasion. For in vivo analysis, we generated Pdx1-Cre; KrasG12D ; Trp53R172H ; Elf3f/f (KPCE) mice and Pdx1-Cre; KrasG12D ; Trp53R172H ; Elf3wt/wt (KPC) mice as a control and analysed their gallbladders histologically. KPCE mice developed larger papillary lesions in the gallbladder than those developed by KPC mice. Organoids established from the gallbladders of KPCE and KPC mice were analysed in vitro. RNA sequencing showed upregulated expression of epiregulin (Ereg) in KPCE organoids, and western blotting revealed that EGFR/mechanical targets of rapamycin complex 1 (mTORC1) were upregulated in KPCE organoids. In addition, ChIP assays on Elf3-overexpressing KPCE organoids showed that ELF3 directly regulated Ereg. Ereg deletion in KPCE organoids (using CRISPR/Cas9) induced EGFR/mTORC1 downregulation, indicating that ELF3 controlled EGFR/mTORC1 activity through regulation of Ereg expression. We also generated allograft mouse models using KPCE and KPC organoids and found that KPCE organoid allograft tumours exhibited poorly differentiated structures with mTORC1 upregulation and mesenchymal phenotype, which were suppressed by Ereg deletion. Furthermore, EGFR/mTORC1 inhibition suppressed cell proliferation and epithelial-mesenchymal transition in KPCE organoids. Our results suggest that ELF3 suppresses GBC development via downregulation of EREG/EGFR/mTORC1 signalling. EGFR/mTORC1 inhibition is a potential therapeutic option for GBC with ELF3 mutation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Insights
Loss-of-function mutations in E74-like ETS transcription factor 3 (ELF3) are common in gallbladder cancer (GBC). ELF3 suppresses GBC by downregulating EREG/EGFR/mTORC1 signaling, suggesting EGFR/mTORC1 inhibition as a potential therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Gallbladder cancer (GBC) has a poor prognosis, necessitating a deeper understanding of its molecular drivers.
- Loss-of-function mutations in E74-like ETS transcription factor 3 (ELF3) are frequently identified in GBC and suggest a tumor suppressor role.
Purpose of the Study:
- To elucidate the molecular mechanisms by which ELF3 suppresses GBC development.
- To investigate the clinical significance of ELF3 expression in human GBC tissues.
Main Methods:
- Utilized autochthonous and allograft mouse models (KPCE and KPC mice) for in vivo analysis.
- Performed histological analysis, organoid culture, RNA sequencing, western blotting, and ChIP assays.
- Employed CRISPR/Cas9 for gene deletion and assessed the effects of EGFR/mTORC1 inhibition.
Main Results:
- Low ELF3 expression correlated with advanced GBC stage and deep tumor invasion.
- ELF3 loss in mouse models led to increased papillary lesions and upregulated epiregulin (Ereg) and EGFR/mTORC1 signaling.
- ELF3 directly regulates Ereg, controlling EGFR/mTORC1 activity; Ereg deletion suppressed tumor progression and mesenchymal phenotype.
- EGFR/mTORC1 inhibition reduced cell proliferation and epithelial-mesenchymal transition in GBC organoids.
Conclusions:
- ELF3 acts as a tumor suppressor in GBC by downregulating the EREG/EGFR/mTORC1 signaling pathway.
- Targeting EGFR/mTORC1 signaling presents a potential therapeutic strategy for GBC patients with ELF3 mutations.
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