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

Abstract

Background and aimsPancreatic 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.MethodsThe 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.ResultsGABRP 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.ConclusionsOverexpressed 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.

Distinct diagnostic and prognostic values of γ‑aminobutyric acid type A receptor family genes in patients with colon adenocarcinoma

“…Sung et al found that GABRP enhances aggressive phenotype of ovarian cancer cells (58). Jiang et al found that the expression of GABRP in pancreatic cancer tissues was significantly increased and associated with poor prognosis, contributing to tumor growth and metastasis (59). In our study, we found that the expression of GABRP in cancer tissues was higher than in adjacent normal tissues and high expression of GABRP are associated with poor prognosis of patients with COAD, which were consistent with the previous studies.…”

RETRACTED ARTICLE: SETDB1 promotes glioblastoma growth via CSF-1-dependent macrophage recruitment by activating the AKT/mTOR signaling pathway

“…Particularly, the presence of symbiosis between macrophages and tumor cells has been shown by experiments where coculture of these cells caused the degradation of collagen [44]. Previous study has shown that macrophage recruitment plays a key role in GABRP-mediated tumor progression in pancreatic cancer [45]. TAMs also involved in tumor growth in glioblastoma [45,46].…”

CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target

“…Promote tumor angiogenesis and lymphangiogenesis in TME [51,52] Regulate the function of neutrophil in TME [45] Positively related to the risk of metastasis [62,63,72] Recruit immune cells -Recruit neutrophils in TME and metastatic niche [30,[42][43][44][45] -Recruit granulocytes to promote the formation of early metastatic microenvironment [40,49] -Promote MDSCs infiltration in TME [47,48] -Positively related to the extent of macrophage infiltration in TME [50] Promote cell proliferation of primary tumors [26,[54][55][56][57] Abbreviations: CXCL5, CXC motif ligand 5; TME, tumor microenvironment; MDSC, myeloid-derived suppressor cell.…”

“…A low expression of CXCL5 in tissues has been found to reduce the recruitment of tumor-associated lymphocytes [9]. Also, CXCL5 has been associated with the degree of macrophage infiltration in primary organs, participating in innate immune responses and is considered important for immunotherapy [50].…”