PT  - JOURNAL ARTICLE
AU  - Shu-Heng Jiang
AU  - Li-Li Zhu
AU  - Man Zhang
AU  - Rong-Kun Li
AU  - Qin Yang
AU  - Jiang-Yu Yan
AU  - Ce Zhang
AU  - Jian-Yu Yang
AU  - Fang-Yuan Dong
AU  - Miao Dai
AU  - Li-Peng Hu
AU  - Jun Li
AU  - Qing Li
AU  - Ya-Hui Wang
AU  - Xiao-Mei Yang
AU  - Yan-Li Zhang
AU  - Hui-Zhen Nie
AU  - Lei Zhu
AU  - Xue-Li Zhang
AU  - Guang-Ang Tian
AU  - Xiao-Xin Zhang
AU  - Xiao-Yan Cao
AU  - Ling-Ye Tao
AU  - Shan Huang
AU  - Yong-Sheng Jiang
AU  - Rong Hua
AU  - Kathy Qian Luo
AU  - Jian-Ren Gu
AU  - Yong-Wei Sun
AU  - Shangwei Hou
AU  - Zhi-Gang Zhang
TI  - GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca<sup>2+</sup> signalling in a GABA-independent manner
AID  - 10.1136/gutjnl-2018-317479
DP  - 2019 Nov 01
TA  - Gut
PG  - 1994--2006
VI  - 68
IP  - 11
4099  - http://gut.bmj.com/content/68/11/1994.short
4100  - http://gut.bmj.com/content/68/11/1994.full
SO  - Gut2019 Nov 01; 68
AB  - 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.