UM
GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner
Jiang,Shu Heng1,2; Zhu,Li Li1; Zhang,Man3; Li,Rong Kun4; Yang,Qin1; Yan,Jiang Yu5; Zhang,Ce1; Yang,Jian Yu2; Dong,Fang Yuan6; Dai,Miao7; Hu,Li Peng1; Li,Jun1; Li,Qing1; Wang,Ya Hui1; Yang,Xiao Mei1; Zhang,Yan Li1; Nie,Hui Zhen1; Zhu,Lei1; Zhang,Xue Li1; Tian,Guang Ang1; Zhang,Xiao Xin1; Cao,Xiao Yan1; Tao,Ling Ye2; Huang,Shan8; Jiang,Yong Sheng2; Hua,Rong2; Qian Luo,Kathy9; Gu,Jian Ren1; Sun,Yong Wei2; Hou,Shangwei10; Zhang,Zhi Gang1
2019
Source PublicationGut
ISSN0017-5749
Volume68Issue:11Pages:1994-2006
AbstractBackground 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 Ca 2+ 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.
KeywordGABA KPC Macrophage Pancreatic cancer Pancreatic intraepithelial neoplasia
DOI10.1136/gutjnl-2018-317479
URLView the original
Language英語English
Scopus ID2-s2.0-85062346556
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Cited Times [WOS]:33   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.State Key Laboratory of Oncogenes and Related Genes,Shanghai Cancer Institute,Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,1111 XianXia road,200336,China
2.Departmentof Biliary-Pancreatic Surgery,RenJi Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,1630 Dongfang road,200217,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,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,Affiliated Cancer Hospital,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,Macao
10.Hongqiao International Institute of Medicine,Tongren Hospital,Shanghai Jiao Tong University,School of Medicine,Shanghai,200240,China
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GB/T 7714
Jiang,Shu Heng,Zhu,Li Li,Zhang,Man,et al. GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner[J]. Gut,2019,68(11):1994-2006.
APA Jiang,Shu Heng.,Zhu,Li Li.,Zhang,Man.,Li,Rong Kun.,Yang,Qin.,Yan,Jiang Yu.,Zhang,Ce.,Yang,Jian Yu.,Dong,Fang Yuan.,Dai,Miao.,Hu,Li Peng.,Li,Jun.,Li,Qing.,Wang,Ya Hui.,Yang,Xiao Mei.,Zhang,Yan Li.,Nie,Hui Zhen.,Zhu,Lei.,Zhang,Xue Li.,...&Zhang,Zhi Gang.(2019).GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner.Gut,68(11),1994-2006.
MLA Jiang,Shu Heng,et al."GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner".Gut 68.11(2019):1994-2006.
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