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Gut. 2019 Mar 2. pii: gutjnl-2018-317479. doi: 10.1136/gutjnl-2018-317479. [Epub ahead of print]

GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner.

Author information

1
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
2
Departmentof Biliary-Pancreatic Surgery, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
3
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
4
Department of Interventional Radiology, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
5
Key Laboratory for Cellular Physiology of Ministry of Education, Department of Neurobiology, Shanxi Medical University, Taiyuan, Shanxi Province, China.
6
Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
7
Department of Gynecologic Oncology, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China.
8
College of Animal Science, Jilin University, Changchun, China.
9
Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
10
Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
#
Contributed equally

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.

KEYWORDS:

GABA; KPC; macrophage; pancreatic cancer; pancreatic intraepithelial neoplasia

PMID:
30826748
DOI:
10.1136/gutjnl-2018-317479

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