Expression of gamma-aminobutyric acid receptors on neoplastic growth and prediction of prognosis in non-small cell lung cancer

Abstract

BackgroundGamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the adult mammalian brain, but exerts physiologic effects other than that on neurotransmitter in non-neuronal peripheral tissues and organs. GABA may affect cancer growth through activation GABA receptors. We investigated the gene expression of GABA receptors in tissue of non-small cell lung cancers (NSCLC) and non-cancerous tissues, and found that the gene expression of GABA receptor phenotypes was correlated with tumorigenesis and clinical prognosis.MethodsSixty-one snap-frozen human samples of NSCLC tissues and paired non-cancerous tissues (5cm away from tumor) were analyzed. Gene expression of GABA receptors was detected by Real-time quantitative PCR (RT-qPCR). Survival times in relation to the expression of GABA receptor phenotypes were analyzed. Human NSCLC cell lines H1299, A549, H520, H460 and human bronchial epithelial cell line BEAS-2B were used to determine the phenotypes of GABA inhibitory effects on cancer cell growth. The effects of exogenous administration of GABA on H1299 cell growth were examined.ResultsThe gene expressions were significantly higher in NSCLC tissues than in the paired non-cancerous tissues for GABAA receptor subunit α3 (GABRA3, P = 0.030); for GABAA receptor subunit epsilon (GABRE, P = 0.036); and GABAB receptor subunit 2 (GABBR2, P = 0.005). Kaplan-Meier curves showed that patients with high expression of GABBR2 gene and low expression of GABRA3 gene had a better prognosis (P < 0.05). The administration of GABA resulted in suppressed proliferation of NSCLC cell lines in a dose- and time-dependent manner. The use of the GABA receptor antagonist CGP35348 could reverse the inhibitory effect.ConclusionsThe pattern of GABA receptor gene phenotype expression may be involved in the regulation of tumorigenesis. A high expression of GABBR2 with a low expression of GABRA3 may predict a better outcome. The treatment with GABA attenuates cancer cell growth in vitro. The expression of GABA receptor may be not only promising genetic therapeutic targets but may also serve as valuable prognostic markers for NSCLC.

Hypermethylation of theGABRE∼miR-452∼miR-224Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy

“…Moreover, although one earlier study has reported upregulation of miR-452 in prostate cancer progenitor cells (17), differential expression in prostate cancer patient samples has not been previously described. There are no prior reports of GABRE deregulation in prostate cancer, but upregulation has been reported in non-small cell lung cancer (34).…”

Genome-wide DNA Methylation Analysis Reveals GABBR2 as a Novel Epigenetic Target for EGFR 19 Deletion Lung Adenocarcinoma with Induction Erlotinib Treatment

“…Similarly, by using a whole-transcript expression array, Schulten and colleagues found that expression of GABBR2 was significantly upregulated in the follicular variant of PTC (35). Notably, the gene expression levels of GABBR2 were also significantly higher in NSCLC tissue than in the paired paracancerous tissue, and patients with high expression of GABBR2 gene had a better prognosis (36). However, the relationship between the methylation status of GABBR2 gene and EGFR-TKI response in lung cancer has not been well investigated before.…”

“…The intronic DMR may block transcription elongation of GABBR2 through affecting histone deacetylation and chromatin structure (31,32) and downregulate gene expression by regulating the methyl-sensitive binding of transcription factors (33). The relationship between GABBR2 and cancer development and prognosis has been considered in several studies (34)(35)(36). The possible role of GABBR2 in cancer progression was first reported by Stein and colleagues and increased expression of GABBR2 was demonstrated in papillary thyroid carcinomas (PTC) using gene expression profiling (34).…”

Repurposing established cyclic adenosine monophosphate reducing agents for the prevention and therapy of epidermal growth factor receptor inhibitor resistance in non-small cell lung cancer

“…It has thus been shown that incidental β-blocker therapy significantly improved survival in NSCLC patients (35) while overexpression of the G i -coupled GABA B -R was associated with a better prognosis (36). In light of the prominent role of β2-ARs in the reported regulation of EGFR inhibitor resistance (19) the correct choice of β-blockers for this approach is of key importance.…”