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Original research
KLHL21 suppresses gastric tumourigenesis via maintaining STAT3 signalling equilibrium in stomach homoeostasis
  1. Xiao-Bo Huang1,2,3,
  2. Qiang Huang1,2,3,
  3. Mei-Chen Jiang4,
  4. Qing Zhong1,2,3,
  5. Hua-Long Zheng1,2,3,
  6. Jia-Bin Wang1,2,3,
  7. Ze-Ning Huang1,2,3,
  8. Hua-Gen Wang1,2,3,
  9. Zhi-Yu Liu1,2,3,
  10. Yi-Fan Li1,2,3,
  11. Kai-Xiang Xu1,2,3,
  12. Mi Lin1,2,3,
  13. Ping Li1,2,3,
  14. Zhi-Hong Huang5,
  15. Jian-Wei Xie1,2,3,
  16. Jian-Xian Lin1,2,3,
  17. Jun Lu1,2,3,
  18. Jian-Wen Que6,7,8,
  19. Chao-Hui Zheng1,2,3,
  20. Qi-Yue Chen1,2,3,
  21. Chang-Ming Huang1,2,3
  1. 1Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
  2. 2Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
  3. 3Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fujian, China
  4. 4Diagnostic Pathology, Fujian Medical University Union Hospital, Fuzhou, China
  5. 5Public Technology Service Center, Fujian Medical University, Fuzhou, China
  6. 6Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
  7. 7Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
  8. 8Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
  1. Correspondence to Professor Chang-Ming Huang, Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; hcmlr2002{at}163.com; Professor Qi-Yue Chen, Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; 690934662{at}qq.com; Professor Chao-Hui Zheng, Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China; wwkzch{at}163.com

Abstract

Objective Precancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood.

Design An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21-floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms.

Results Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1+ cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy.

Conclusions Our findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs.

  • GASTRIC CANCER
  • DNA DAMAGE
  • STEM CELLS
  • CHEMOTHERAPY
  • CELL SIGNALLING

Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. The RIP-seq and polysome-seq data that provide evidence for the findings presented in this study have been deposited in the Gene Expression Omnibus under the accession number GSE163310. The source of the mouse scRNA-seq data was downloaded from the National Center for Biotechnology Information under the accession number SRP227356.

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Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. The RIP-seq and polysome-seq data that provide evidence for the findings presented in this study have been deposited in the Gene Expression Omnibus under the accession number GSE163310. The source of the mouse scRNA-seq data was downloaded from the National Center for Biotechnology Information under the accession number SRP227356.

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Footnotes

  • X-BH, QH, M-CJ and QZ are joint first authors.

  • Correction notice This article has been corrected since it published Online First. The funding information has been amended and affiliation number 4.

  • Contributors X-BH, QH, Q-YC and C-MH conceived the study, analysed the data and drafted the manuscript. M-CJ analysed the histological slides. QZ performed animal dissections and tissue manipulations. C-MH, Q-YC, C-HZ and J-WQ critically revised the manuscript for important intellectual content. H-LZ, J-BW, Z-NH, H-GW, ML, PL, Z-HH, J-WX, J-XL and JL assisted in data collection and study design. All authors read and approved the final manuscript. C-MH acts as guarantor of the article.

  • Funding This study was supported by the National Natural Science Foundation of China (No 81871899, 82372606); Construction Project of Fujian Province Minimally Invasive Medical Center (No (2021)76); the Natural Science Foundation of Fujian Province (No 2020J011001, 2022J06021); Science and Technology Innovation Joint Fund Project of Fujian Province (No 2023Y9174); the Graduate Innovation Project of Sailing Fund of Fujian Medical University (2021QH2027); Fujian provincial health technology project (No 2023GGA016) and Excellent Young Scholars Cultivation Project of Fujian Medical University Union Hospital (2022XH021, 2022XH041).

  • 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.