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.

Nonalcoholic fatty liver disease (NAFLD), a metabolic disorder related to insulin resistance and metabolic syndrome, has become a public health concern. Currently, the principal therapeutic modalities targeting NAFLD are lifestyle interventions. However, the efficacy of long-term lifestyle interventions in managing NAFLD remains largely unexplored. This study aimed to evaluate the efficacy of long-term lifestyle interventions in middle-aged and elderly men with NAFLD. All 280 eligible patients were randomized to the control or test group. Patients in the test group received counseling on diet and exercise from 2 physicians every 3 months via a phone call. Patients in the control group received only counseling in annual checkups without regular intervention. After the 2-year periodic intervention, body weight, abdominal circumference, ALT, TCH, LDL-C and HDL-C decreased in the test group. Specifically, the fatty liver index (FLI) and NAFLD-fibrosis score (NAFLD-FS) reduced markedly in the test group. However, in the control group, there was only a significant decrease in LDL-C, HDL-C and NAFLD-FS (P < 0.001). The liver steatosis grade of the test group decreased significantly, while it increased in the control group. In NAFLD, long-term lifestyle interventions exert an anti-obesity effect and attenuate liver dysfunction and steatosis.