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Current Genomics


ISSN (Print): 1389-2029
ISSN (Online): 1875-5488

Research Article

Prostate Cancer Gene Regulatory Network Inferred from RNA-Seq Data

Author(s): Daniel Moore, Ricardo de Matos Simoes, Matthias Dehmer and Frank Emmert-Streib*

Volume 20, Issue 1, 2019

Page: [38 - 48] Pages: 11

DOI: 10.2174/1389202919666181107122005


Background: Cancer is a complex disease with a lucid etiology and in understanding the causation, we need to appreciate this complexity.

Objective: Here we are aiming to gain insights into the genetic associations of prostate cancer through a network-based systems approach using the BC3Net algorithm.

Methods: Specifically, we infer a prostate cancer Gene Regulatory Network (GRN) from a large-scale gene expression data set of 333 patient RNA-seq profiles obtained from The Cancer Genome Atlas (TCGA) database.

Results: We analyze the functional components of the inferred network by extracting subnetworks based on biological process information and interpret the role of known cancer genes within each process. Furthermore, we investigate the local landscape of prostate cancer genes and discuss pathological associations that may be relevant in the development of new targeted cancer therapies.

Conclusion: Our network-based analysis provides a practical systems biology approach to reveal the collective gene-interactions of prostate cancer. This allows a close interpretation of biological activity in terms of the hallmarks of cancer.

Keywords: Gene regulatory network, Prostate cancer, Genomics, Systems biology, Network inference, Precision medicine, Data science.

Graphical Abstract
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: IARC Cancer Base No. 11; IARC Publications 2013, 2013.
Patel, A.R.; Klein, E.A. Risk factors for prostate cancer. Nat. Clin. Pract. Urol., 2009, 6(2), 87-95.
Chodak, G. Prostate cancer: Epidemiology, screening, and biomarkers. Rev. Urol., 2006, 8(2), S3-S8.
Quaresma, M.; Coleman, M.P.; Rachet, B. 40-year trends in an index of survival for all cancers combined and survival adjusted for age and sex for each cancer in England and Wales, 1971-2011: A population-based study. Lancet, 2015, 385(9974), 1206-1218.
Dong, J.T. Prevalent mutations in prostate cancer. J. Cell. Biochem., 2006, 97(3), 433-447.
Wang, E.; Lenferink, A.; O’Connor-McCourt, M. Cancer systems biology: Exploring cancer-associated genes on cellular networks. Cell. Mol. Life Sci., 2007, 64(14), 1752-1762.
Kreeger, P.K.; Lauffenburger, D.A. Cancer systems biology: A network modeling perspective. Carcinogenesis, 2010, 31(1), 2-8.
de Matos Simoes, R.; Tripathi, S.; Emmert-Streib, F. Organizational structure of the peripheral gene regulatory network in B-cell lymphoma. BMC Syst. Biol., 2012, 6, 38.
de Matos Simoes, R.; Dehmer, M.; Emmert-Streib, F. B-cell lymphoma gene regulatory networks: Biological consistency among inference methods. Front. Genet., 2013, 4, 281.
Emmert-Streib, F.; de Matos Simoes, R.; Glazko, G.; McDade, S.; Haibe-Kains, B.; Holzinger, A.; Dehmer, M.; Campbell, F. Functional and genetic analysis of the colon cancer network. BMC Bioinformatics, 2014, 15(Suppl. 6), S6.
Emmert-Streib, F.; de Matos Simoes, R.; Mullan, P.; Haibe-Kains, B.; Dehmer, M. The gene regulatory network for breast cancer: Integrated regulatory landscape of cancer hallmarks. Front. Genet., 2014, 5, 15.
de Matos Simoes, R.; Emmert-Streib, F. Bagging statistical network inference from large-scale gene expression data. PLoS One, 2012, 7(3), e33624.
Hecker, M.; Lambeck, S.; Toepfer, S.; van Someren, E.; Guthke, R. Gene regulatory network inference: Data integration in dynamic models - A review. Biosystems, 2009, 96(1), 86-103.
Hartemink, A.J. Reverse engineering gene regulatory networks. Nat. Biotechnol., 2005, 23(5), 554-555.
Emmert-Streib, F.; Dehmer, M.; Haibe-Kains, B. Untangling statistical and biological models to understand network inference: The need for a genomics network ontology. Front. Genet., 2014, 5, 299.
Emmert-Streib, F.; Dehmer, M.; Haibe-Kains, B. Gene regulatory networks and their applications: Understanding biological and medical problems in terms of networks. Front. Cell Dev. Biol., 2014, 2, 38.
Wang, Y.; Joshi, T.; Zhang, X-S.; Xu, D.; Chen, L. Inferring gene regulatory networks from multiple microarray datasets. Bioinformatics, 2006, 22(19), 2413-2420.
Li, B.; Ruotti, V.; Stewart, R.M.; Thomson, J.A.; Dewey, C.N. RNA-seq gene expression estimation with read mapping uncertainty. Bioinformatics, 2010, 26(4), 493-500.
Newton, M.A.; Kendziorski, C.M.; Richmond, C.S.; Blattner, F.R.; Tsui, K.W. On differential variability of expression ratios: Improving statistical inference about gene expression changes from microarray data. J. Comput. Biol., 2001, 8(1), 37-52.
Altay, G.; Emmert-Streib, F. Structural influence of gene networks on their inference: Analysis of c3net. Biol. Direct, 2011, 6(1), 31.
Futreal, P.A.; Coin, L.; Marshall, M.; Down, T.; Hubbard, T.; Wooster, R.; Rahman, N.; Stratton, M.R. A census of human cancer genes. Nat. Rev. Cancer, 2004, 4(3), 177-183.
Dijkstra, E.W. A note on two problems in connexion with graphs. Numerische Mathematik., 1959, 1(1), 269-271.
de Matos Simoes, R.; Dehmer, M.; Emmert-Streib, F. Interfacing cellular networks of S. cerevisiae and E. coli: Connecting dynamic and genetic information. BMC Genomics, 2013, 14(1), 324.
Gentleman, R.C.; Carey, V.J.; Bates, D.M.; Bolstad, B.; Dettling, M.; Dudoit, S.; Ellis, B.; Gautier, L.; Ge, Y.; Gentry, J.; Hornik, K.; Hothorn, T.; Huber, W.; Iacus, S.; Irizarry, R.; Leisch, F.; Li, C.; Maechler, M.; Rossini, A.J.; Sawitzki, G.; Smith, C.; Smyth, G.; Tierney, L.; Yang, J.Y.; Zhang, J. Bioconductor: Open software development for computational biology and bioinformatics. Genome Biol., 2004, 5(10), R80.
Elis, W.; Triantafellow, E.; Wolters, N.M.; Sian, K.R.; Caponigro, G.; Borawski, J.; Gaither, L.A.; Murphy, L.O.; Finan, P.M.; Mackeigan, J.P. Down-regulation of class ii phosphoinositide 3-kinase α expression below a critical threshold induces apoptotic cell death. Mol. Cancer Res., 2008, 6(4), 614-623.
Vivanco, I.; Sawyers, C.L. The phosphatidylinositol 3-kinase-akt pathway in human cancer. Nat. Rev. Cancer, 2002, 2(7), 489-501.
Cantley, L.C. The phosphoinositide 3-kinase pathway. Science, 2002, 296(5573), 1655-1657.
Di Lorenzo, G.; Tortora, G.; D’Armiento, F.P.; De Rosa, G.; Staibano, S.; Autorino, R.; D’Armiento, M.; De Laurentiis, M.; De Placido, S.; Catalano, G.; Bianco, A.R.; Ciardiello, F. Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin. Cancer Res., 2002, 8(11), 3438-3444.
Platz, E.A.; Pollak, M.N.; Leitzmann, M.F.; Stampfer, M.J.; Willett, W.C.; Giovannucci, E. Plasma insulin- like growth factor-1 and binding protein-3 and subsequent risk of prostate cancer in the PSA era. Cancer Causes Control, 2005, 16(3), 255-262.
Chan, J.M.; Stampfer, M.J.; Giovannucci, E.; Gann, P.H.; Ma, J.; Wilkinson, P.; Hennekens, C.H.; Pollak, M. Plasma insulin-like growth factor-i and prostate cancer risk: a prospective study. Science, 1998, 279(5350), 563-566.
Bhatia-Gaur, R.; Donjacour, A.A.; Sciavolino, P.J.; Kim, M.; Desai, N.; Young, P.; Norton, C.R.; Gridley, T.; Cardiff, R.D.; Cunha, G.R.; Abate-Shen, C.; Shen, M.M. Roles for nkx3.1 in prostate development and cancer. Genes Dev., 1999, 13(8), 966-977.
Eagle, L.R.; Yin, X.; Brothman, A.R.; Williams, B.J.; Atkin, N.B.; Prochownik, E.V. Mutation of the mxi1 gene in prostate cancer. Nat. Genet., 1995, 9(3), 249-255.
Umbas, R.; Isaacs, W.B.; Bringuier, P.P.; Schaafsma, H.E.; Karthaus, H.F.; Oosterhof, G.O.; Debruyne, F.M.; Schalken, J.A. Decreased e-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res., 1994, 54(14), 3929-3933.
Kleinerman, D.I.; Troncoso, P.; Lin, S.H.; Pisters, L.L.; Sherwood, E.R.; Brooks, T.; von Eschenbach, A.C.; Hsieh, J.T. Consistent expression of an epithelial cell adhesion molecule (c-cam) during human prostate development and loss of expression in prostate cancer: Implication as a tumor suppressor. Cancer Res., 1995, 55(6), 1215-1220.
Wolk, A.; Mantzoros, C.S.; Andersson, S.O.; Bergström, R.; Signorello, L.B.; Lagiou, P.; Adami, H.O.; Trichopoulos, D. Insulin-like growth factor 1 and prostate cancer risk: A population-based, case-control study. J. Natl. Cancer Inst., 1998, 90(12), 911-915.
Wikström, P.; Stattin, P.; Franck-Lissbrant, I.; Damber, J.E.; Bergh, A. Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate, 1998, 37(1), 19-29.
Olapade-Olaopa, E.O.; Moscatello, D.K.; MacKay, E.H.; Horsburgh, T.; Sandhu, D.P.; Terry, T.R.; Wong, A.J.; Habib, F.K. Evidence for the differential expression of a variant EGF receptor protein in human prostate cancer. Br. J. Cancer, 2000, 82(1), 186-194.
Oren, M. Decision making by p53: Life, death and cancer. Cell Death Differ., 2003, 10(4), 431-442.
Farnebo, M.; Bykov, V.J.; Wiman, K.G. The p53 tumor suppressor: a master regulator of diverse cellular processes and therapeutic target in cancer. Biochem. Biophys. Res. Commun., 2010, 396(1), 85-89.
Enari, M.; Ohmori, K.; Kitabayashi, I.; Taya, Y. Requirement of clathrin heavy chain for p53-mediated transcription. Genes Dev., 2006, 20(9), 1087-1099.
Shimada, H.; Matsubara, H.; Shiratori, T.; Shimizu, T.; Miyazaki, S.; Okazumi, S.; Nabeya, Y.; Shuto, K.; Hayashi, H.; Tanizawa, T.; Nakatani, Y.; Nakasa, H.; Kitada, M.; Ochiai, T. Phase i/ii adenovi- ral p53 gene therapy for chemoradiation resistant advanced esophageal squamous cell carcinoma. Cancer Sci., 2006, 97(6), 554-561.
Ventura, A.; Kirsch, D.G.; McLaughlin, M.E.; Tuveson, D.A.; Grimm, J.; Lintault, L.; Newman, J.; Reczek, E.E.; Weissleder, R.; Jacks, T. Restoration of p53 function leads to tumour regression in vivo. Nature, 2007, 445(7128), 661-665.
Varambally, S.; Dhanasekaran, S.M.; Zhou, M.; Barrette, T.R.; Kumar-Sinha, C.; Sanda, M.G.; Ghosh, D.; Pienta, K.J.; Sewalt, R.G.; Otte, A.P.; Rubin, M.A.; Chinnaiyan, A.M. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature, 2002, 419(6907), 624-629.
Bryant, R.J.; Cross, N.A.; Eaton, C.L.; Hamdy, F.C.; Cunliffe, V.T. EZH2 promotes proliferation and invasiveness of prostate cancer cells. Prostate, 2007, 67(5), 547-556.
Choi, J.H.; Song, Y.S.; Yoon, J.S.; Song, K.W.; Lee, Y.Y. Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation and metastasis in gastric cancer. APMIS, 2010, 118(3), 196-202.
Yan, M.; Xu, H.; Waddell, N.; Shield-Artin, K.; Haviv, I. kCon Fab, authors; McKay, M.J.; Fox, S.B. Enhanced RAD21 cohesin expression confers poor prognosis in BRCA2 and BRCAX, but not BRCA1 familial breast cancers. Breast Cancer Res., 2012, 14(2), R69.
Mitra, A.V.; Bancroft, E.K.; Barbachano, Y.; Page, E.C.; Foster, C.S.; Jameson, C.; Mitchell, G.; Lindeman, G.J.; Stapleton, A.; Suthers, G.; Evans, D.G.; Cruger, D.; Blanco, I.; Mercer, C.; Kirk, J.; Maehle, L.; Hodgson, S.; Walker, L.; Izatt, L.; Douglas, F.; Tucker, K.; Dorkins, H.; Clowes, V.; Male, A.; Donaldson, A.; Brewer, C.; Doherty, R.; Bulman, B.; Osther, P.J.; Salinas, M.; Eccles, D.; Axcrona, K.; Jobson, I.; Newcombe, B.; Cybulski, C.; Rubinstein, W.S.; Buys, S.; Townshend, S.; Friedman, E.; Domchek, S.; Ramon, Y.; Cajal, T.; Spigelman, A.; Teo, S.H.; Nicolai, N.; Aaronson, N.; Ardern-Jones, A.; Bangma, C.; Dearnaley, D.; Eyfjord, J.; Falconer, A.; Grönberg, H.; Hamdy, F.; Johannsson, O.; Khoo, V.; Kote-Jarai, Z.; Lilja, H.; Lubinski, J.; Melia, J.; Moynihan, C.; Peock, S.; Rennert, G.; Schröder, F.; Sibley, P.; Suri, M.; Wilson, P.; Bignon, Y.J.; Strom, S.; Tischkowitz, M.; Liljegren, A.; Ilencikova, D.; Abele, A.; Kyriacou, K.; van Asperen, C.; Kiemeney, L. IMPACT Study Collaborators Easton, D.F.; Eeles, R.A. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: Preliminary analysis of the results of the IMPACT study. BJU Int., 2011, 107(1), 28-39.
de Visser, K.E.; Eichten, A.; Coussens, L.M. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer, 2006, 6(1), 24-37.
Vasto, S.; Carruba, G.; Candore, G.; Italiano, E.; Di Bona, D.; Caruso, C. Inflammation and prostate cancer. Future Oncol., 2008, 4(5), 637-645.
Weiss, T.W.; Simak, R.; Kaun, C.; Rega, G.; Pflüger, H.; Maurer, G.; Huber, K.; Wojta, J. Oncostatin M and IL-6 induce u-PA and VEGF in prostate cancer cells and correlate in vivo. Anticancer Res., 2011, 31(10), 3273-3278.
Ellis, L.M.; Hicklin, D.J. VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nat. Rev. Cancer, 2008, 8(8), 579-591.
Meyer-Siegler, K.L.; Iczkowski, K.A.; Leng, L.; Bucala, R.; Vera, P.L. Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells. J. Immunol., 2006, 177(12), 8730-8739.
Ciavarra, R.P.; Somers, K.D.; Brown, R.R.; Glass, W.F.; Consolvo, P.J.; Wright, G.L.; Schellhammer, P.F. Flt3-ligand induces transient tumor regression in an ectopic treatment model of major histocompatibility complex-negative prostate cancer. Cancer Res., 2000, 60(8), 2081-2084.
Huang, S.P.; Lan, Y.H.; Lu, T.L.; Pao, J.B.; Chang, T.Y.; Lee, H.Z.; Yang, W.H.; Hsieh, C.J.; Chen, L.M.; Huang, L.C.; Ting, W.C.; Bao, B.Y. Clinical significance of runt-related transcription factor 1 polymorphism in prostate cancer. BJU Int., 2011, 107(3), 486-492.
Deb, S.; Huiling, X.; Thorne, H.; Willems-Jones, A.; Clouston, D.; Bolton, D.; Ramsay, R.; Fox, S.B. Rad21 overexpression is frequently observed in BRCA-X prostate cancers. Hered. Cancer Clin. Pract., 2012, 10(Suppl. 2), A59.
Zhan, P.; Ji, Y.N.; Yu, L.K. VEGF is associated with the poor survival of patients with prostate cancer: A meta-analysis. Transl. Androl. Urol., 2013, 2(2), 99-105.
Wang, Y.Z.; Wong, Y.C. Sex hormone-induced prostatic carcinogenesis in the noble rat: The role of insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) in the development of prostate cancer. Prostate, 1998, 35(3), 165-177.
Zhong, H.; Semenza, G.L.; Simons, J.W.; De Marzo, A.M. Up-regulation of hypoxia-inducible factor 1α is an early event in prostate carcinogenesis. Cancer Detect. Prev., 2004, 28(2), 88-93.
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell, 2000, 100(1), 57-70.
R Core Team.R: A Language and Environment for Statistical Computing; R Foundation for Statistical Computing: Vienna, Austria, 2014.

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