GABRD Accelerates Tumour Progression via Regulating CCND1 Signalling Pathway in Gastric Cancer

Neurotransmitters and their receptors were reported to be involved in tumour initiation and progression. However, little is known about their roles in gastric cancer (GC). Here, we first identified gamma-aminobutyric acid type A receptor subunit delta (GABRD) as a novel oncogene in GC. GABRD was preferentially upregulated in GC tissues compared with adjacent normal tissues. High GABRD expression was significantly associated with poor survival prognosis. Knockdown of GABRD could markedly induce cell apoptosis and cell cycle arrest while repressing proliferation and migration in vitro, and suppress tumour growth in vivo. The results of transcriptomic analysis and Ingenuity pathway analysis (IPA) highlighted that cyclin D1(CCND1) was a potential downstream target. Immunohistochemistry results also indicated that CCND1 expression was associated with GABRD in GC. Functional experiments also confirmed that the role of GABRD in regulating proliferation, migration, invasion, and apoptosis was dependent on CCND1. Mechanically, further research confirmed that GABRD knockdown could induce p53-dependent apoptosis through CCND1, and GABRD upregulated CCDN1 through inhibiting its ubiquitin-mediated degradation. Overall, these findings uncover a role for the neurotransmitter receptor GABRD in regulating the proliferation and apoptosis of gastric cancer cells. Our present study provides novel insights into the mechanism of tumourigenesis in gastric cancer.