Gamma-Aminobutyric Acid Type A Receptor Subunit Delta (GABRD) Inhibits Breast Cancer Progression by Regulating the Cell Cycle
Abstract
Background: The role of γ-aminobutyric acid receptor (GABR) in breast cancer (BC) is unknown.
Methods: The expression of different GABR subunits between BC and adjacent normal tissues was compared using transcriptome data set. The clinical and prognostic importance of the various GABR subunit genes in BC was determined using clinical and survival data (Data downloaded from TCGA, May 2022). Only GABRD was discovered to be substantially expressed and strongly related to the prognosis of BC cases.
Results: Compared with normal tissues, GABRD expression was increased in all subgroups of breast cancer tissues. Knockdown of GABRD inhibited the growth of BC cells. Mechanistically, the function of GABRD may be attributed to its effect on major pathways such as oxidative phosphorylation, Parkinson disease, and cell cycle. GABRD deletion significantly blocked the G2/M phase in BC cells.
Conclusion: Overall, GABRD might be a novel prognostic predictor of BC, providing clues for further studies on GABRD.
1. Sung H, Ferlay J, Siegel RL, et al (2021). Glob-al Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Coun-tries. CA Cancer J Clin, 71(3):209-249.
2. Ferlay J, Ervik M, Lam F, et al (2020). Global Cancer Obser-Vatory: Cancer Today. In-ternational Agency for Research on Can-cer; Lyon, France: 2020. [(accessed on 9 July 2021)]. Available online: https://gco.iarc.fr/today.
3. Ginsburg O, Yip CH, Brooks A, et al (2020). Breast cancer early detection: A phased approach to implementation. Cancer, 126:2379-2393.
4. Santucci C, Carioli G, Bertuccio P, et al (2020). Progress in cancer mortality, incidence, and survival: a global overview. Eur J Can-cer Prev, 29(5):367-381.
5. Deepak KGK, Vempati R, Nagaraju GP,et al (2020). Tumor microenvironment: Chal-lenges and opportunities in targeting me-tastasis of triple negative breast cancer. Pharmacol Res, 153:104683.
6. Mahvi DA, Liu R, Grinstaff MW, Colson YL, Raut CP (2018). Local Cancer Recurrence: The Realities, Challenges, and Opportuni-ties for New Therapies. CA Cancer J Clin, 68(6):488-505.
7. Sigel E, Steinmann ME (2012). Structure, function, and modulation of GABA(A) receptors. J Biol Chem, 287(48):40224-40231.
8. Steiger JL, Russek SJ (2004). GABAA recep-tors: building the bridge between subunit mRNAs, their promoters, and cognate transcription factors. Pharmacol Ther, 101(3):259-81.
9. Wisden W, Seeburg PH (1992). GABAA re-ceptor channels: from subunits to func-tional entities. Curr Opin Neurobiol, 2(3):263-9.
10. Korpi ER, Sinkkonen ST (2006). GABA(A) receptor subtypes as targets for neuro-psychiatric drug development. Pharmacol Ther, 109(1-2):12-32.
11. Macdonald RL, Kang JQ, Gallagher MJ (2010). Mutations in GABAA receptor subunits associated with genetic epilep-sies. J Physiol, 588(Pt 11):1861-9.
12. Bloss CS, Berrettini W, Bergen AW, et al (2011). Genetic association of recovery from eating disorders: the role of GABA receptor SNPs. Neuropsychopharmacology, 36(11):2222-2232.
13. Collins AL, Ma D, Whitehead PL, et al (2006). Investigation of autism and GABA receptor subunit genes in multiple ethnic groups. Neurogenetics, 7(3):167-174.
14. Ament SA, Szelinger S, Glusman G, et al (2015). Rare variants in neuronal excitabil-ity genes influence risk for bipolar disor-der. Proc Natl Acad Sci U S A, 112(11):3576-3581.
15. Cancer Genome Atlas Research Network, Weinstein JN, Collisson EA, et al (2013). The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet, 45(10):1113-1120.
16. Robinson MD, McCarthy DJ, Smyth GK (2010). edgeR: a Bioconductor package for differential expression analysis of dig-ital gene expression data. Bioinformatics, 26(1):139-140.
17. Zee J, Xie SX (2018). The Kaplan-Meier Method for Estimating and Comparing Proportions in a Randomized Controlled Trial with Dropouts. Biostat Epidemiol, 2(1):23-33.
18. Anaya J, Reon B, Chen WM, Bekiranov S, Dutta A (2016). A pan-cancer analysis of prognostic genes. PeerJ, 3:e1499.
19. Ito K, Murphy D (2013). Application of ggplot2 to Pharmacometric Graphics. CPT Pharmacometrics Syst Pharmacol, 2(10):e79.
20. Chen L, Zhang YH, Wang S, Zhang Y, Huang T, Cai YD (2017). Prediction and analysis of essential genes using the en-richments of gene ontology and KEGG pathways. PLoS One, 12(9):e0184129.
21. Subramanian A, Tamayo P, Mootha VK, et al (2005). Gene set enrichment analysis: a knowledge-based approach for interpret-ing genome-wide expression profiles. Proc Natl Acad Sci U S A, 102(43):15545-15550.
22. Tsherniak A, Vazquez F, Montgomery PG, et al (2017). Defining a Cancer Depend-ency Map. Cell, 170(3):564-576.e16.
23. Yaqi L, Mei L, Zhuoxian Z et al (2021). QSOX2 Is an E2F1 Target Gene and a Novel Serum Biomarker for Monitoring Tumor Growth and Predicting Survival in Advanced NSCLC. Front Cell Dev Biol, 9:688798.
24. Feng Y, Kapornai K, Kiss E, et al (2010). Association of the GABRD gene and childhood-onset mood disorders. Genes Brain Behav, 9(6):668-672.
25. Dibbens LM, Feng HJ, Richards MC, et al (2004). GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet, 13(13):1315-1319.
26. Bujko M, Kober P, Boresowicz J, et al (2019). USP8 mutations in corticotroph adenomas determine a distinct gene ex-pression profile irrespective of functional tumour status. Eur J Endocrinol, 181(6):615-627.
27. Gross AM, Kreisberg JF, Ideker T (2015). Analysis of Matched Tumor and Normal Profiles Reveals Common Transcription-al and Epigenetic Signals Shared across Cancer Types. PLoS One, 10(11):e0142618.
28. Zhang H, Zhang L, Tang Y, et al (2019). Systemic screening identifies GABRD, a subunit gene of GABAA receptor as a prognostic marker in adult IDH wild-type diffuse low-grade glioma. Biomed Pharma-cother, 118:109215.
29. Zhang B, Wu Q, Xu R, et al (2019). The promising novel biomarkers and candi-date small molecule drugs in lower-grade glioma: Evidence from bioinformatics analysis of high-throughput data. J Cell Biochem, 120(9):15106-15118.
30. Sarathi A, Palaniappan A (2019). Novel sig-nificant stage-specific differentially ex-pressed genes in hepatocellular carcino-ma. BMC Cancer, 19(1):663.
31. Wu M, Kim KY, Park WC, et al (2020). En-hanced expression of GABRD predicts poor prognosis in patients with colon adenocarcinoma. Transl Oncol, 13(12):100861.
32. Ingham M, Schwartz GK (2017). Cell-Cycle Therapeutics Come of Age. J Clin Oncol, 35(25):2949-2959.
2. Ferlay J, Ervik M, Lam F, et al (2020). Global Cancer Obser-Vatory: Cancer Today. In-ternational Agency for Research on Can-cer; Lyon, France: 2020. [(accessed on 9 July 2021)]. Available online: https://gco.iarc.fr/today.
3. Ginsburg O, Yip CH, Brooks A, et al (2020). Breast cancer early detection: A phased approach to implementation. Cancer, 126:2379-2393.
4. Santucci C, Carioli G, Bertuccio P, et al (2020). Progress in cancer mortality, incidence, and survival: a global overview. Eur J Can-cer Prev, 29(5):367-381.
5. Deepak KGK, Vempati R, Nagaraju GP,et al (2020). Tumor microenvironment: Chal-lenges and opportunities in targeting me-tastasis of triple negative breast cancer. Pharmacol Res, 153:104683.
6. Mahvi DA, Liu R, Grinstaff MW, Colson YL, Raut CP (2018). Local Cancer Recurrence: The Realities, Challenges, and Opportuni-ties for New Therapies. CA Cancer J Clin, 68(6):488-505.
7. Sigel E, Steinmann ME (2012). Structure, function, and modulation of GABA(A) receptors. J Biol Chem, 287(48):40224-40231.
8. Steiger JL, Russek SJ (2004). GABAA recep-tors: building the bridge between subunit mRNAs, their promoters, and cognate transcription factors. Pharmacol Ther, 101(3):259-81.
9. Wisden W, Seeburg PH (1992). GABAA re-ceptor channels: from subunits to func-tional entities. Curr Opin Neurobiol, 2(3):263-9.
10. Korpi ER, Sinkkonen ST (2006). GABA(A) receptor subtypes as targets for neuro-psychiatric drug development. Pharmacol Ther, 109(1-2):12-32.
11. Macdonald RL, Kang JQ, Gallagher MJ (2010). Mutations in GABAA receptor subunits associated with genetic epilep-sies. J Physiol, 588(Pt 11):1861-9.
12. Bloss CS, Berrettini W, Bergen AW, et al (2011). Genetic association of recovery from eating disorders: the role of GABA receptor SNPs. Neuropsychopharmacology, 36(11):2222-2232.
13. Collins AL, Ma D, Whitehead PL, et al (2006). Investigation of autism and GABA receptor subunit genes in multiple ethnic groups. Neurogenetics, 7(3):167-174.
14. Ament SA, Szelinger S, Glusman G, et al (2015). Rare variants in neuronal excitabil-ity genes influence risk for bipolar disor-der. Proc Natl Acad Sci U S A, 112(11):3576-3581.
15. Cancer Genome Atlas Research Network, Weinstein JN, Collisson EA, et al (2013). The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet, 45(10):1113-1120.
16. Robinson MD, McCarthy DJ, Smyth GK (2010). edgeR: a Bioconductor package for differential expression analysis of dig-ital gene expression data. Bioinformatics, 26(1):139-140.
17. Zee J, Xie SX (2018). The Kaplan-Meier Method for Estimating and Comparing Proportions in a Randomized Controlled Trial with Dropouts. Biostat Epidemiol, 2(1):23-33.
18. Anaya J, Reon B, Chen WM, Bekiranov S, Dutta A (2016). A pan-cancer analysis of prognostic genes. PeerJ, 3:e1499.
19. Ito K, Murphy D (2013). Application of ggplot2 to Pharmacometric Graphics. CPT Pharmacometrics Syst Pharmacol, 2(10):e79.
20. Chen L, Zhang YH, Wang S, Zhang Y, Huang T, Cai YD (2017). Prediction and analysis of essential genes using the en-richments of gene ontology and KEGG pathways. PLoS One, 12(9):e0184129.
21. Subramanian A, Tamayo P, Mootha VK, et al (2005). Gene set enrichment analysis: a knowledge-based approach for interpret-ing genome-wide expression profiles. Proc Natl Acad Sci U S A, 102(43):15545-15550.
22. Tsherniak A, Vazquez F, Montgomery PG, et al (2017). Defining a Cancer Depend-ency Map. Cell, 170(3):564-576.e16.
23. Yaqi L, Mei L, Zhuoxian Z et al (2021). QSOX2 Is an E2F1 Target Gene and a Novel Serum Biomarker for Monitoring Tumor Growth and Predicting Survival in Advanced NSCLC. Front Cell Dev Biol, 9:688798.
24. Feng Y, Kapornai K, Kiss E, et al (2010). Association of the GABRD gene and childhood-onset mood disorders. Genes Brain Behav, 9(6):668-672.
25. Dibbens LM, Feng HJ, Richards MC, et al (2004). GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet, 13(13):1315-1319.
26. Bujko M, Kober P, Boresowicz J, et al (2019). USP8 mutations in corticotroph adenomas determine a distinct gene ex-pression profile irrespective of functional tumour status. Eur J Endocrinol, 181(6):615-627.
27. Gross AM, Kreisberg JF, Ideker T (2015). Analysis of Matched Tumor and Normal Profiles Reveals Common Transcription-al and Epigenetic Signals Shared across Cancer Types. PLoS One, 10(11):e0142618.
28. Zhang H, Zhang L, Tang Y, et al (2019). Systemic screening identifies GABRD, a subunit gene of GABAA receptor as a prognostic marker in adult IDH wild-type diffuse low-grade glioma. Biomed Pharma-cother, 118:109215.
29. Zhang B, Wu Q, Xu R, et al (2019). The promising novel biomarkers and candi-date small molecule drugs in lower-grade glioma: Evidence from bioinformatics analysis of high-throughput data. J Cell Biochem, 120(9):15106-15118.
30. Sarathi A, Palaniappan A (2019). Novel sig-nificant stage-specific differentially ex-pressed genes in hepatocellular carcino-ma. BMC Cancer, 19(1):663.
31. Wu M, Kim KY, Park WC, et al (2020). En-hanced expression of GABRD predicts poor prognosis in patients with colon adenocarcinoma. Transl Oncol, 13(12):100861.
32. Ingham M, Schwartz GK (2017). Cell-Cycle Therapeutics Come of Age. J Clin Oncol, 35(25):2949-2959.
| Files | ||
| Issue | Vol 52 No 3 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v52i3.12137 | |
| Keywords | ||
| γ-aminobutyric acid receptor Breast cancer Prognosis Growth Cell cycle | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Wu L, Zhang Y, Zheng C, Zhao F, Lin Y. Gamma-Aminobutyric Acid Type A Receptor Subunit Delta (GABRD) Inhibits Breast Cancer Progression by Regulating the Cell Cycle. Iran J Public Health. 2023;52(3):542-552.
