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Original article
GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner
  1. Shu-Heng Jiang1,2,
  2. Li-Li Zhu1,
  3. Man Zhang3,
  4. Rong-Kun Li4,
  5. Qin Yang1,
  6. Jiang-Yu Yan5,
  7. Ce Zhang,
  8. Jian-Yu Yang2,
  9. Fang-Yuan Dong6,
  10. Miao Dai7,
  11. Li-Peng Hu1,
  12. Jun Li1,
  13. Qing Li1,
  14. Ya-Hui Wang1,
  15. Xiao-Mei Yang1,
  16. Yan-Li Zhang1,
  17. Hui-Zhen Nie1,
  18. Lei Zhu1,
  19. Xue-Li Zhang1,
  20. Guang-Ang Tian1,
  21. Xiao-Xin Zhang1,
  22. Xiao-Yan Cao1,
  23. Ling-Ye Tao2,
  24. Shan Huang8,
  25. Yong-Sheng Jiang2,
  26. Rong Hua2,
  27. Kathy Qian Luo9,
  28. Jian-Ren Gu1,
  29. Yong-Wei Sun2,
  30. Shangwei Hou10,
  31. Zhi-Gang Zhang1
  1. 1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  2. 2Departmentof Biliary-Pancreatic Surgery, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  3. 3Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
  4. 4Department of Interventional Radiology, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  5. 5Key Laboratory for Cellular Physiology of Ministry of Education, Department of Neurobiology, Shanxi Medical University, Taiyuan, Shanxi Province, China
  6. 6Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China
  7. 7Department of Gynecologic Oncology, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
  8. 8College of Animal Science, Jilin University, Changchun, China
  9. 9Faculty of Health Sciences, University of Macau, Taipa, Macau, China
  10. 10Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  1. Correspondence to Dr Yong-Wei Sun, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200217, China; syw0616{at}126.com, Dr Shangwei Hou, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai 200336, China; housw{at}sjtu.edu.cn and Professor Zhi-Gang Zhang, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China; zzhang{at}shsci.org

Abstract

Background and aims Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis.

Methods The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism.

Results GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression.

Conclusions Overexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

  • pancreatic cancer
  • GABA
  • macrophage
  • pancreatic intraepithelial neoplasia
  • KPC

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Footnotes

  • S-HJ, L-LZ, MZ, R-KL and QY contributed equally.

  • Contributors S-HJ, L-LZ and R-KL carried out in vitro cell experiments, in vivo experiments, manuscript preparation and statistical analysis; QY contributed to bioinformatics analysis; J-YY, L-YT, Y-SJ and RH provided clinical specimens and made clinical pathology evaluations; MZ, CZ and J-YY performed electrophysiological testing; L-PH, JL and Y-HW contributed to animal breeding; F-YD, MD, QL, G-AT, X-XZ, X-YC and SH performed western blot analysis and IHC analysis; X-MY, Y-LZ, H-ZN, LZ, X-LZ and K-QL provided critical review; J-RG, S-WH, Y-WS and Z-GZ conceived, designed, supervised, analysed and interpreted the study and provided critical review.

  • Funding This work was supported by grants from National Natural Science Foundation of China (81871923, 81802890, 81872242, 81502382, 81500461 and 81761138045), the Natural Science Foundation of Shanghai (17ZR1428300 and 18ZR1436900), Shanghai Municipal Commission of Health and Family Planning (201740105), Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20181708), Shanghai Municipal Health Bureau (2018BR32) and the State Key Laboratory of Oncogenes and Related Genes (no 91-17-14).

  • Competing interests None declared.

  • Ethics approval The study was approved by the Research Ethics Committee of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. The experiments were approved by the Research Ethics Committee of East China Normal University.

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

  • Correction notice This article has been corrected since it published Online First. Figure 4 has been replaced with the correct figure and the equal contribution statement has been added.

  • Patient consent for publication Obtained.

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