Expression of gamma-aminobutyric acid receptors on neoplastic growth and prediction of prognosis in non-small cell lung cancer
© Zhang et al.; licensee BioMed Central Ltd. 2013
Received: 28 December 2012
Accepted: 16 April 2013
Published: 24 April 2013
Gamma-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.
Sixty-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.
The 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.
The 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.
KeywordsGamma aminobutyric acid receptor Survival Biomarker Prognosis
Cancer is a major global public health problem. One in 4 deaths in the United States is due to cancer . Lung cancer is comprising 17% of the total new cancer cases and 23% of the total cancer deaths . Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancer cases where adenocarcinoma is dominantly presented . Conventional treatment of NSCLC has improved survival, but the 5-year survival rate is approximately 16% over the past 30 years . Novel and effective methods are urgently required for lung cancer therapy.
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the adult mammalian brain via activation of specific GABA receptors highly expressed in the central nervous system (CNS) [4, 5]. GABA receptors are composed of GABAA and GABAB receptors. GABAA receptors are ligand-gated chloride channels composed of five subunits. These subunits are encoded by 19 different genes that have been grouped into eight subclasses based on sequence homology (α1–6, β1–3, γ1–3, δ, ϵ, θ, π, ρ1–3). GABAB receptors are heterodimeric G-protein-coupled receptors (GPCRs) composed of GABBR1 and GABBR2 subunits which are both required for normal receptor functioning .
It has recently revealed that GABA and its receptors also exist in non-neuronal peripheral tissues and organs, indicating that GABA exerts physiologic effects other than the inhibitory neurotransmitter property. In fact, GABA has been shown to be involved in the development of many tissues and organs, including the peripheral nervous system , the development of the palate , lung , pancreas , digestive tract , liver , chondrocytes , testicular cells  and even stem cells .
Given that GABA participates in the proliferation of various normal cell types and tissues, it is intriguing to consider the potential function of GABA in cancer cells. Recent studies gave the evidences that GABA and its receptors seemed to play critically regulative effects on many kinds of cancers [12, 16–31]. In most cases, the levels of GABA receptors accompanying other growth signaling components had significant changes in cancer cells. This raised the possibility that manipulating GABA receptor activity might inhibit tumor growth .
In this study, we tested the hypothesis that GABA receptor profiles modulate cancer survival. We thus investigated the gene expression of GABA receptor phenotypes in NSCLC tissues and paired non-cancerous tissues obtained from surgical patients to correlate the GABA receptor gene profiles with clinical outcome. To examine the specific effects of GABA receptor on lung cancer cell growth, we investigated the GABA receptor profiles in cancer cell lines and in normal human epithelial cell line in the presence and absence of exogenous administration of GABA.
Cancer cell lines
Human NSCLC cell lines H1299(adenocarcinoma), A549(adenocarcinoma), H520(squamous cell carcinoma), H460(large cell carcinoma) and normal human bronchial epithelial cell line BEAS-2B (ATCC, Rockville, Maryland) were cultured at 37°C with 5% CO2 in DMEM (Gibco, Beijing, China) supplemented with 10% FBS (Gibco, Beijing, China) without antibiotics.
MTT assays for cell proliferation
To measure the proliferation of cells, the colorimetric 3-(4, 5-dimethyle thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assays (Sigma) were used in vitro. In the MTT assays, cells were seeded into 96-well plates (2 × 103 cells per well), grown overnight, washed in PBS, and incubated with GABA (Sigma-Aldrich) at 0.1 μmol/L to 500 μmol/L in the presence or absence of 100 μmol/L picrotoxin (PTX, GABAA receptor antagonist) or CGP35348 (CGP, GABAB receptor antagonist), respectively. MTT was then added (10ug/well) for 4h. Formazan products were solubilized with DMSO, and the optical density was measured at 490 nm.
Tissues and subjects
Sixty-one samples of NSCLC tissues and paired non-cancerous tissues (5cm away from tumor) were collected from the Thoracic Cardio Surgery Department of the First Affiliated Hospital of Guangzhou Medical College under full ethical clearance by the Guangzhou Medical College Ethics Committee for experimentation on human subjects. Informed written consent was obtained from the participants. All subjects were Chinese. The collected samples were immediately cut into small pieces and snap-frozen in liquid nitrogen until further use. All tumor tissue and paired non-cancerous tissue samples were pathologically confirmed.
RNA extraction and cDNA synthesis
Total RNA from cell lines and liquid-nitrogen-frozen NSCLC tissue samples were extracted using Trizol reagent (Invitrogen). First-strand cDNAs were synthesized using primerscript RT reagent kit (Takara). Briefly, a mix of 2 ug RNA, 2 μl of 5× gDNA eraser buffer and 1 μl of gDNA eraser in a final volume of 10 μl with RNase free DH2O, was incubated at 42°C for 2 min to get rid of gDNA, and placed on ice for at least 1 min. Then 4 μL 5× Primerscript buffer, 1 μL Primerscript RT enzyme mix I, 1 μL RT primer mix, and 3 μL RNase free DH2O were added, and incubated at 37°C for 15 min followed by 85°C for 5 sec. The cDNA samples were stored at -20°C until use.
Primer sequences, NCBI gene ID and amplicon size
NCBI gene ID
Amplicon size (bp)
PCR was performed to pick out the genes expression in NSCLC cancer cell lines using Premix Taq® version 2.0 kit (Takara). The reaction condition was followed: initial denaturation at 95°C for 1 min; 35 cycles of 30 sec at 95°C; 30 sec at 58°C; and 30 sec at 72°C; followed by a final 3 min extension at 72°C. 3% Agarose gel was used in electrophoresis to separate the reaction products at 80V, 40min. After dyeing with ethidium bromide, the Gel Doc™ EZ Imager (BIO-RAD) was used for imaging.
Real-time quantitative PCR was carried out in tissues cDNA samples using the SYBR® Premix Ex Taq™ reagent kit (Takara) through ABI PRISM®7900 HT Fast Real-Time PCR system (Applied Biosystems). Briefly, 2 μl of each cDNA product was amplified in a mixture containing 12.5 μl of 2 × SYBR® Premix Ex Taq™, 0.5 μl of 10 μmol/L PCR sense primer and the same quantitative antisense primer with dH2O in a final volume of 25 μL. The RT-qPCR was performed using the following parameters: initial denaturation at 95°C for 30 sec, 40 cycles of 5 s at 95°C, 30 s at 60°C. The dissolved curve was added to verify the specificity of amplified products. Wells with no template were included for each primer set as a negative control. In each experiment, samples were amplified in duplicate for each of the genes of interest and the reference gene. Only average CT values with a standard deviation <0.5 were accepted.
The expression of each gene of interest was determined in relation to the reference gene 18S rRNA. The difference in the mean CT values of the duplicate samples against the reference gene was calculated to give the ΔCT. The relative quantitation value was then expressed as two times -ΔCT (2–ΔCT). Analysis of the 2–ΔCT values data was performed using SPSS 13.0 followed by Paired-Samples t Test and Independent-Samples t Test where appropriate. Correlation analysis was carried out for GABA concentration and cell growth over time. Survival times between groups were displayed by Kaplan-Meier curves after a log-rank test. P<0.05 was considered statistical significance.
Effect of GABA on cancer cell proliferation
GABA receptor profiles in NSCLC cell lines
GABA receptor profiles in NSCLC tissues and paired non-cancerous tissues
Comparison of GABA receptor gene relative expression between cancer and paired non-cancerous tissue
Normal(n = 61)
Cancer(n = 61)
1.647 ± 0.394
3.681 ± 0.853
2.054 ± 0.276
3.767 ± 0.883
0.940 ± 0.236
3.315 ± 0.868
3.585 ± 1.163
3.103 ± 0.792
3.147 ± 0.475
4.095 ± 0.760
3.693 ± 0.538
3.413 ± 0.976
Survival analysis in relation to GABA receptor gene profiles
GABA receptors profiles and selected clinical characteristics
GABRA3, GABRE and GABBR2 gene expression in NSCLC tissues compare with paired non-cancerous tissues
Squamous cell carcinoma
GABA and GABA receptors act as an inhibitory neurotransmitter in the mature CNS, but their functions in non-neuronal cells or tumor cells are not well addressed. Previous investigation has reported that GABA is significantly decreased in NSCLC tissues . The previous observation maybe explained by our current findings demonstrating that GABA exerts inhibitory effects on human NSCLC cell. Our results further demonstrate that GABAB receptors play an important role in mediating the GABA-inhibitory effects on NSCLC cells since the effects were blocked by using the antagonist CGP35348 specific for GABAB receptor. Decreased GABA level might have resulted in impaired inhibitory effects on cancer cell proliferation as seen clinically . A compensatory mechanism may be required by enhancing the expression of GABAB receptors in order to redeem the impaired inhibitory effects.
The etiological factors of lung cancer are still not clear, but the tumor progression is associated with genetic changes and is reflected in phenotypic changes such as altered gene expression profiles. In this study, we found that the six genes of GABA receptors are expressed in most of NSCLC cells and tissues, including GABRA3, GABRB3, GABRE, GABRP, GABBR1 and GABBR2. These subunits might compose functional GABAA and GABAB receptor. These genetic changes suggest that GABA receptors have close relationship with NSCLC progression.
As for GABAB receptors, it is now well accepted that GABAB receptors assemble into heteromers composed of one GABBR1 and one GABBR2 subunit, which are both required for normal receptor function [6, 32]. Some recent reports have suggested that GABA inhibits neoplastic proliferation via GABAB receptor [23, 26]. Since GABAB receptor could strongly inhibit base level and isoproterenol-induced cAMP, p-CREB, cyclic adenosine monophosphate response element-luciferase activity and p-extracellular regulated kinase-1 (ERK1)/2 and effectively blocked DNA synthesis and cell migration. The inhibitory cancer cells arrest in G(0)/G(1) phase which is associated with down-regulation of intracellular cAMP level . In our study, GABA inhibited proliferation of NSCLC cells in a dose-dependent and a time-dependent manner. This inhibitory effect could be blocked in the presence of GABAB receptor inhibitor CGP35348. However, co-cultured with GABAA receptor inhibitor picrotoxin, there were no significant proliferative effects on cancer cells versus control. These results imply that GABA inhibition of NSCLC cell proliferation was associated with GABAB receptor which coincides with the report by Schuller and Al-Wadei [23, 26]. The high level expression of GABAB receptor gene in NSCLC tissues compared with the adjacent non-tumor lung tissues, implicated that GABA and GABAB receptor pathways could be a critical factor in regulation of NSCLC cells proliferation. This pathway might be a promising molecular target for the development of new therapeutic strategies for antineoplaston.
As for GABAA receptors, it has been demonstrated that GABAA receptors are usually composed of two α subunits, two β subunits, and one γ subunit, and sometime the γ subunit is replaced by other subunits, such as δ, ϵ, π and θ . Different GABAA receptor subunits have been detected in many cancer cell lines and tissues. Li et al.  detected overexpression of GABRQ in hepatocellular carcinoma cell line HepG2, and half of the tested hepatocellular carcinoma tissues. Takehara  identified the overexpression of GABA receptor pi subunit (GABRP) in PDAC cells. In gastric cancer, more than five GABAA receptor subunits were associated with stimulating KATO III cells . The similar results that GABAA receptors are related to cancer cell proliferation were reported in prostate cancer , breast carcinoma , even in normal human small airway epithelial cells . These findings imply that the inward Cl— ionic current transport and the activated mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) cascade via GABAA receptors positively promotes cell proliferation. Our study revealed that the GABRA3 receptor gene was overexpression in NSCLC tissues compare with paired non-cancerous tissues, this was consistent with the study reported by Liu et al. . In addition, beside overexpression of GABRA3 and GABRE genes, the other GABAA receptor genes expression in our study including GABRB3 and GABRP were also detected in lung cancers, although there was no significant difference between NSCLC tissues and paired non-cancerous tissues. These GABAA receptor subunits may form a functional pentameric chloride channel. We observe that the overexpression GABRA3 and GABRE genes were not associated with proliferative effects on cancer cells. This indecipherable phenomenon will lend us to take more investigations of their roles in lung cancers.
Furthermore, our clinical data analysis showed that both GABAA receptors (GABRA3) and GABAB receptor (GABBR2) genes were significantly expressed in the early pathological stage (stage I and II) of the lung cancer patients, and the expression was gone in stage III and IV. This suggests that high level of gene expression of these GABA receptors may be critical in inhibition of early stage of cancer cells and this regulatory effect got impaired in advanced stage. We speculate that therapeutic intervention approaches that enhance GABA receptors maybe beneficial in late stages of NSCLC patients.
We observe a correlation between the high expression of GABBR2 gene and the greater survival rate in patients with NSCLC. The overexpression of GABBR2 gene was mostly seen in female patients who had better outcome. This suggests that patients with higher level GABBR2 might have better outcome. This observation is consistent with previous in vitro data showing that high level GABBR2 gene expression is associated with inhibition of cancer cell proliferation [26, 39, 40].
In contrast, high level GABRA3 gene expression is correlated with cancer cell development [12, 35, 41], and thus these patients had worse outcome. We indeed showed that the higher gene expression of GABRA3 was mostly detected in those male patients who had a worse prognosis.
Our data was based on a relatively small sample size of 61 patients with NSCLC who were followed for 3–5 years. Our data suggests that the gene expression of certain GABA receptor subunits may be useful for prediction of NSCLC prognosis. We believe that a longer term follow-up study with larger sample size would be required to confirm our current findings.
The present study has identified significant gene profiles of GABA receptors in NSCLC and the gene profiles are correlated with patients’ survival. Exogenous administration of GABA can inhibit NSCLC growth by activation on GABA receptors. Our data suggests that GABA receptors can modulate cancer cell proliferation and their gene profiles may be able to help predict prognosis in patients with NSCLC.
The authors thank Mo Lili for valuable help with preparation of the tissue samples and all members in He Jianxing’s lab for their technical assistance.
- Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 2012, 62: 10-29. 10.3322/caac.20138.View ArticlePubMedGoogle Scholar
- Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322/caac.20107.View ArticlePubMedGoogle Scholar
- Custodio A, Mendez M, Provencio M: Targeted therapies for advanced non-small-cell lung cancer: current status and future implications. Cancer Treat Rev. 2012, 38: 36-53. 10.1016/j.ctrv.2011.04.001.View ArticlePubMedGoogle Scholar
- Sieghart W: Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol Rev. 1995, 47: 181-234.PubMedGoogle Scholar
- Kerr DI, Ong J: GABAB receptors. Pharmacol Ther. 1995, 67: 187-246. 10.1016/0163-7258(95)00016-A.View ArticlePubMedGoogle Scholar
- Bettler B, Kaupmann K, Mosbacher J, Gassmann M: Molecular structure and physiological functions of GABA(B) receptors. Physiol Rev. 2004, 84: 835-867. 10.1152/physrev.00036.2003.View ArticlePubMedGoogle Scholar
- Magnaghi V, Ballabio M, Cavarretta IT, Froestl W, Lambert JJ, Zucchi I, Melcangi RC: GABAB receptors in Schwann cells influence proliferation and myelin protein expression. Eur J Neurosci. 2004, 19: 2641-2649. 10.1111/j.0953-816X.2004.03368.x.View ArticlePubMedGoogle Scholar
- Ding R, Tsunekawa N, Obata K: Cleft palate by picrotoxin or 3-MP and palatal shelf elevation in GABA-deficient mice. Neurotoxicol Teratol. 2004, 26: 587-592. 10.1016/j.ntt.2004.04.002.View ArticlePubMedGoogle Scholar
- Jin N, Guo Y, Sun P, Bell A, Chintagari NR, Bhaskaran M, Rains K, Baviskar P, Chen Z, Weng T, Liu L: Ionotropic GABA receptor expression in the lung during development. Gene Expr Patterns. 2008, 8: 397-403. 10.1016/j.gep.2008.04.008.PubMed CentralView ArticlePubMedGoogle Scholar
- Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T: GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci USA. 2011, 108: 11692-11697. 10.1073/pnas.1102715108.PubMed CentralView ArticlePubMedGoogle Scholar
- Wang FY, Watanabe M, Zhu RM, Maemura K: Characteristic expression of gamma-aminobutyric acid and glutamate decarboxylase in rat jejunum and its relation to differentiation of epithelial cells. World J Gastroenterol. 2004, 10: 3608-3611.PubMed CentralView ArticlePubMedGoogle Scholar
- Li YH, Liu Y, Li YD, Liu YH, Li F, Ju Q, Xie PL, Li GC: GABA stimulates human hepatocellular carcinoma growth through overexpressed GABAA receptor theta subunit. World J Gastroenterol. 2012, 18: 2704-2711. 10.3748/wjg.v18.i21.2704.PubMed CentralView ArticlePubMedGoogle Scholar
- Tamayama T, Maemura K, Kanbara K, Hayasaki H, Yabumoto Y, Yuasa M, Watanabe M: Expression of GABA(A) and GABA(B) receptors in rat growth plate chondrocytes: activation of the GABA receptors promotes proliferation of mouse chondrogenic ATDC5 cells. Mol Cell Biochem. 2005, 273: 117-126. 10.1007/s11010-005-8159-6.View ArticlePubMedGoogle Scholar
- Kanbara K, Okamoto K, Nomura S, Kaneko T, Shigemoto R, Azuma H, Katsuoka Y, Watanabe M: Cellular localization of GABA and GABAB receptor subunit proteins during spermiogenesis in rat testis. J Androl. 2005, 26: 485-493. 10.2164/jandrol.04185.View ArticlePubMedGoogle Scholar
- Andang M, Hjerling-Leffler J, Moliner A, Lundgren TK, Castelo-Branco G, Nanou E, Pozas E, Bryja V, Halliez S, Nishimaru H: Histone H2AX-dependent GABA(A) receptor regulation of stem cell proliferation. Nature. 2008, 451: 460-464. 10.1038/nature06488.View ArticlePubMedGoogle Scholar
- Lukasiewicz PD, Shields CR: A diversity of GABA receptors in the retina. Semin Cell Dev Biol. 1998, 9: 293-299. 10.1006/scdb.1998.0238.View ArticlePubMedGoogle Scholar
- Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H: GABA and GABA receptors in the central nervous system and other organs. Int Rev Cytol. 2002, 213: 1-47.View ArticlePubMedGoogle Scholar
- Azuma H, Inamoto T, Sakamoto T, Kiyama S, Ubai T, Shinohara Y, Maemura K, Tsuji M, Segawa N, Masuda H: Gamma-aminobutyric acid as a promoting factor of cancer metastasis; induction of matrix metalloproteinase production is potentially its underlying mechanism. Cancer Res. 2003, 63: 8090-8096.PubMedGoogle Scholar
- Thaker PH, Yokoi K, Jennings NB, Li Y, Rebhun RB, Rousseau DL, Fan D, Sood AK: Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal. Cancer Biol Ther. 2005, 4: 753-758. 10.4161/cbt.4.7.1827.View ArticlePubMedGoogle Scholar
- Watanabe M, Maemura K, Oki K, Shiraishi N, Shibayama Y, Katsu K: Gamma-aminobutyric acid (GABA) and cell proliferation: focus on cancer cells. Histol Histopathol. 2006, 21: 1135-1141.PubMedGoogle Scholar
- Rotondo A, Serio R, Mule F: Functional evidence for different roles of GABAA and GABAB receptors in modulating mouse gastric tone. Neuropharmacology. 2010, 58: 1033-1037. 10.1016/j.neuropharm.2010.01.004.View ArticlePubMedGoogle Scholar
- Al-Wadei HA, Ullah MF, Al-Wadei M: GABA (gamma-aminobutyric acid), a non-protein amino acid counters the beta-adrenergic cascade-activated oncogenic signaling in pancreatic cancer: a review of experimental evidence. Mol Nutr Food Res. 2011, 55: 1745-1758. 10.1002/mnfr.201100229.View ArticlePubMedGoogle Scholar
- Al-Wadei HA, Al-Wadei MH, Schuller HM: Cooperative regulation of non-small cell lung carcinoma by nicotinic and beta-adrenergic receptors: a novel target for intervention. PLoS One. 2012, 7: e29915-10.1371/journal.pone.0029915.PubMed CentralView ArticlePubMedGoogle Scholar
- Schuller HM, Al-Wadei HA: Neurotransmitter receptors as central regulators of pancreatic cancer. Future Oncol. 2010, 6: 221-228. 10.2217/fon.09.171.PubMed CentralView ArticlePubMedGoogle Scholar
- Young SZ, Bordey A: GABA’s control of stem and cancer cell proliferation in adult neural and peripheral niches. Physiology (Bethesda). 2009, 24: 171-185. 10.1152/physiol.00002.2009.View ArticleGoogle Scholar
- Schuller HM, Al-Wadei HA, Majidi M: Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma. Carcinogenesis. 2008, 29: 1979-1985. 10.1093/carcin/bgn041.PubMed CentralView ArticlePubMedGoogle Scholar
- Roberts SS, Mendonca-Torres MC, Jensen K, Francis GL, Vasko V: GABA receptor expression in benign and malignant thyroid tumors. Pathol Oncol Res. 2009, 15: 645-650. 10.1007/s12253-009-9165-x.View ArticlePubMedGoogle Scholar
- Maemura K, Shiraishi N, Sakagami K, Kawakami K, Inoue T, Murano M, Watanabe M, Otsuki Y: Proliferative effects of gamma-aminobutyric acid on the gastric cancer cell line are associated with extracellular signal-regulated kinase 1/2 activation. J Gastroenterol Hepatol. 2009, 24: 688-696. 10.1111/j.1440-1746.2008.05687.x.View ArticlePubMedGoogle Scholar
- Abdul M, McCray SD, Hoosein NM: Expression of gamma-aminobutyric acid receptor (subtype A) in prostate cancer. Acta Oncol. 2008, 47: 1546-1550. 10.1080/02841860801961265.View ArticlePubMedGoogle Scholar
- D’Urso PI, D’Urso OF, Storelli C, Mallardo M, Gianfreda CD, Montinaro A, Cimmino A, Pietro C: Marsigliante S: miR-155 is up-regulated in primary and secondary glioblastoma and promotes tumour growth by inhibiting GABA receptors. Int J Oncol. 2012, 41: 228-234.PubMedGoogle Scholar
- Von Metzler A, Nitsch C: [Effects of 3-methylcholanthrene and 3-methylcholanthrene plus piracetam on the gamma-amino-butyric acid (GABA) content of several cerebral regions (author’s transl)]. J Cancer Res Clin Oncol. 1981, 101: 339-343. 10.1007/BF00410120.View ArticlePubMedGoogle Scholar
- Pinard A, Seddik R, Bettler B: GABAB receptors: physiological functions and mechanisms of diversity. Adv Pharmacol. 2010, 58: 231-255.View ArticlePubMedGoogle Scholar
- Wang T, Huang W, Chen F: Baclofen, a GABAB receptor agonist, inhibits human hepatocellular carcinoma cell growth in vitro and in vivo. Life Sci. 2008, 82: 536-541. 10.1016/j.lfs.2007.12.014.View ArticlePubMedGoogle Scholar
- Olsen RW, Sieghart W: GABA A receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology. 2009, 56: 141-148. 10.1016/j.neuropharm.2008.07.045.PubMed CentralView ArticlePubMedGoogle Scholar
- Takehara A, Hosokawa M, Eguchi H, Ohigashi H, Ishikawa O, Nakamura Y, Nakagawa H: Gamma-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor pi subunit. Cancer Res. 2007, 67: 9704-9712. 10.1158/0008-5472.CAN-07-2099.View ArticlePubMedGoogle Scholar
- Drell TL, Joseph J, Lang K, Niggemann B, Zaenker KS, Entschladen F: Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Trea. 2003, 80: 63-70. 10.1023/A:1024491219366.View ArticleGoogle Scholar
- Xiang YY, Wang S, Liu M, Hirota JA, Li J, Ju W, Fan Y, Kelly MM, Ye B, Orser B: A GABAergic system in airway epithelium is essential for mucus overproduction in asthma. Nat Med. 2007, 13: 862-867. 10.1038/nm1604.View ArticlePubMedGoogle Scholar
- Liu Y, Guo F, Dai M, Wang D, Tong Y, Huang J, Hu J, Li G: Gammaaminobutyric acid A receptor alpha 3 subunit is overexpressed in lung cancer. Pathol Oncol Res. 2009, 15: 351-358. 10.1007/s12253-008-9128-7.View ArticlePubMedGoogle Scholar
- Lodewyks C, Rodriguez J, Yan J, Lerner B, Lipschitz J, Nfon C, Rempel JD, Uhanova J, Minuk GY: GABA-B receptor activation inhibits the in vitro migration of malignant hepatocytes. Can J Physiol Pharmacol. 2011, 89: 393-400. 10.1139/y11-031.View ArticlePubMedGoogle Scholar
- Schuller HM, Al-Wadei HA, Majidi M: GABA B receptor is a novel drug target for pancreatic cancer. Cancer. 2008, 112: 767-778. 10.1002/cncr.23231.PubMed CentralView ArticlePubMedGoogle Scholar
- Liu Y, Li YH, Guo FJ, Wang JJ, Sun RL, Hu JY, Li GC: Gamma-aminobutyric acid promotes human hepatocellular carcinoma growth through overexpressed gamma-aminobutyric acid A receptor alpha 3 subunit. World J Gastroenterol. 2008, 14: 7175-7182. 10.3748/wjg.14.7175.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.