Benign prostatic hyperplasia (BPH) is a commonly occurring disease in aging men. It involves cellular proliferation of stromal and glandular tissues leading to prostate enlargement. Current drug therapies show several adverse effects such as sexual dysfunctions and cardiovascular side effects. Therefore, there is a need to develop more effective medical treatment for BPH. In this regard, we aimed to identify genes which play a critical role in BPH. We have obtained the dataset of differentially expressed genes (DEGs) of BPH from NCBI GEO. DEGs were investigated in the context of their protein-protein interactions (PPI). Hub genes i.e. genes associated with BPH were scrutinized based on the topological parameters of the PPI network. These were analyzed for functional annotations, pathway enrichment analysis and transcriptional regulation. In total, 38 hub genes were identified. Hub genes such as transcription factor activator protein-1 and adiponectin were found to play key roles in cellular proliferation and inflammation. Another gene peroxisome proliferator activated receptor gamma was suggested to cause obesity, a common comorbidity of BPH. Moreover, our results indicated an important role of transforming growth factor-beta (TGF-β) signaling and smooth muscle cell proliferation which may be responsible for prostate overgrowth and associated lower urinary tract symptoms frequently encountered in BPH patients. Zinc finger protein Snai1 was the most prominent transcription factor regulating the expression of hub genes that participate in TGF-β signaling. Overall, our study has revealed significant hub genes that can be employed as drug targets to develop potential therapeutic interventions to treat BPH.
Pagano E, Laudato M, Griffo M, Capasso R. Phytotherapy of benign prostatic hyperplasia. Phytother Res 2014;28:949-955.
Vuichoud C, Loughlin KR. Benign prostatic hyperplasia: epidemiology, economics and evaluation. Can J Urol 2015;22:1-6.
Platz EA, Smit E, Curhan GC, Nyberg LM, Giovannucci E. Prevalence of and racial/ethnic variation in lower urinary tract symptoms and noncancer prostate surgery in U.S. men. Urology 2002;59:877-883.
Izumi K, Mizokami A, Lin WJ, Lai KP, Chang C. Androgen receptor roles in the development of benign prostate hyperplasia. Am J Pathol 2013;182:1942-1949.
Mobley D, Feibus A, Baum N. Benign prostatic hyperplasia and urinary symptoms: evaluation and treatment. Postgrad Med 2015;127:301-307.
Ventura S, Oliver Vl, White CW, Xie JH, Haynes JM, Exintaris B. Novel drug targets for the pharmacotherapy of benign prostatic hyperplasia (BPH). Br J Pharmacol 2011;163:891-907.
Chapple C. Antimuscarinics in men with lower urinary tract symptoms suggestive of bladder outlet obstruction due to benign prostatic hyperplasia. Curr Opin Urol 2010;20:43-48.
Debruyne F, Tzvetkov M, Altarac S, Geavlete PA. Dose-ranging study of the luteinizing hormone-releasing hormone receptor antagonist cetrorelix pamoate in the treatment of patients with symptomatic benign prostatic hyperplasia. Urology 2010;76:927-933.
Gacci M, Ficarra V, Sebastianelli A, Corona G, Serni S, Shariat SF, Maggi M, Zattoni F, Carini M, Novara G. Impact of medical treatments for male lower urinary tract symptoms due to Benign Prostatic Hyperplasia on ejaculatory function: A systematic review and meta-analysis. J Sex Med 2014;11:1554-1566.
Sriroopreddy R, Sajeed R, PR, CS. Differentially expressed gene (DEG) based protein-protein interaction (PPI) network identifies a spectrum of gene interactome, transcriptome and correlated miRNA in nondisjunction Down syndrome. Int J Biol Macromol 2019;122:1080-1089.
Tiwari S, Dwivedi UN. Discovering Innovative Drugs Targeting Both Cancer and Cardiovascular Disease by Shared Protein-Protein Interaction Network Analyses. OMICS 2019;23:417-425.
Xiao H, Jiang Y, He W, Xu D, Chen P, Liu D, Liu J, Wang X, DiSanto ME, Zhang X. Identification and functional activity of matrix-remodeling associated 5 (MXRA5) in benign hyperplastic prostate. Aging (Albany NY) 2020;12:8605-8621.
Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, Mering CV. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019;47:D607-D613.
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13:2498-2504.
Kotlyar M, Pastrello C, Pivetta F, Lo Sardo A, Cumbaa C, Li H, Naranian T, Niu Y, Ding Z, Vafaee F, Broackes-Carter F, Petschnigg J, Mills GB, Jurisicova A, Stagljar I, Maestro R, Jurisica I. In silico prediction of physical protein interactions and characterization of interactome orphans. Nat Methods 2015;12:79-84.
Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pagès F, Trajanoski Z, Galon J. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 2009;25:1091-1093.
Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A, Frisch M, Bayerlein M, Werner T. MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 2005;21:2933-2942.
Hamberg M, Backes C, Fehlmann T, Hart M, Meder B, Meese E, Keller A. MiRTargetLink--miRNAs, Genes and Interaction Networks. Int J Mol Sci 2016;17:564.
Ou Z, He Y, Qi L, Zu X, Wu L, Cao Z, Li Y, Liu L, Dube DA, Wang Z, Wang L. Infiltrating mast cells enhance benign prostatic hyperplasia through IL-6/STAT3/Cyclin D1 signals. Oncotarget 2017;8:59156-59164.
Lin-Tsai O, Clark PE, Miller NL, Fowke JH, Hameed O, Hayward SW, Strand DW. Surgical intervention for symptomatic benign prostatic hyperplasia is correlated with expression of the AP-1 transcription factor network. Prostate 2014;74:669-679.
Trop-Steinberg S, Azar Y. AP-1 expression and its clinical relevance in immune disorders and cancer. Am J Med Sci 2017;353:474-483.
Schenk JM, Kristal AR, Neuhouser ML, Tangen CM, White E, Lin DW, Thompson IM. Serum adiponectin, C-peptide and leptin and risk of symptomatic benign prostatic hyperplasia: results from the Prostate Cancer Prevention Trial. Prostate 2009;69:1303-1311.
DiSanto ME, Stein R, Chang S, Hypolite JA, Zheng Y, Zderic S, Wein AJ, Chacko S. Alteration in expression of myosin isoforms in detrusor smooth muscle following bladder outlet obstruction. Am J Physiol Cell Physiol 2003;285:C1397-C1410.
Sakko AJ, Ricciardelli C, Mayne K, Tilley WD, Lebaron RG, Horsfall DJ. Versican accumulation in human prostatic fibroblast cultures is enhanced by prostate cancer cell-derived transforming growth factor beta1. Cancer Res 2001;61:926-930.
Andersson-Sjöland A, Hallgren O, Rolandsson S, Weitoft M, Tykesson E, Larsson-Callerfelt AK, Rydell-Törmänen K, Bjermer L, Malmström A, Karlsson JC, Westergren-Thorsson G. Versican in inflammation and tissue remodeling: the impact on lung disorders. Glycobiology 2015;25:243-251.
Sreenivasulu K, Nandeesha H, Dorairajan LN, Rajappa M, Vinayagam V, Cherupanakkal C. Gene expression of insulin receptor, insulin-like growth factor increases and insulin-like growth factor-binding protein-3 reduces with increase in prostate size in benign prostatic hyperplasia. Aging Male 2018;21:138-144.
Qian Q, He W, Liu D, Yin J, Ye L, Chen P, Xu D, Liu J, Li Y, Zeng G, Li M, Wu Z, Zhang Y, Wang X, DiSanto ME, Zhang X. M2a macrophage can rescue proliferation and gene expression of benign prostate hyperplasia epithelial and stroma cells from insulin-like growth factor 1 knockdown. Prostate 2021;81:530-542.
Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ. Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 2008;10:295-305.
Li SH, Ryu JH, Park SE, Cho YS, Park JW, Lee WJ, Chun YS. Vitamin C supplementation prevents testosterone-induced hyperplasia of rat prostate by down-regulating HIF-1alpha. J Nutr Biochem 2010;21:801-808.
Kim HJ, Park JW, Cho YS, Cho CH, Kim JS, Shin HW, Chung DH, Kim SJ, Chun YS. Pathogenic role of HIF-1α in prostate hyperplasia in the presence of chronic inflammation. Biochim Biophys Acta 2013;1832:183-194.
Rosen ED, Spiegelman BM. PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 2001;276:37731-37734.
Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994;79:1147-1156.
Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999;4:611-617.
Kristal AR, Arnold KB, Schenk JM, Neuhouser ML, Weiss N, Goodman P, Antvelink CM, Penson DF, Thompson IM. Race/ethnicity, obesity, health related behaviors and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. J Urol 2007;177:1395-1400.
Wang L, Xie L, Tintani F, Xie H, Li C, Cui Z, Wan M, Zu X, Qi L, Cao X. Aberrant Transforming Growth Factor-β Activation Recruits Mesenchymal Stem Cells During Prostatic Hyperplasia. Stem Cells Transl Med 2017;6:394-404.
Schilit S, Benzeroual KE. Silodosin: a selective alpha1A-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia. Clin Ther 2009;31:2489-2502.
Mónica FZ, De Nucci G. Tadalafil for the treatment of benign prostatic hyperplasia. Expert Opin Pharmacother 2019;20:929-937.
)