Oncogene-tumor suppressor gene feedback interactions and their control

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2015, 12(6): 1277-1288. doi: 10.3934/mbe.2015.12.1277

Oncogene-tumor suppressor gene feedback interactions and their control

Baltazar D. Aguda ^1, , Ricardo C.H. del Rosario ^2, and Michael W.Y. Chan ^3,

1.	DiseasePathways LLC, Bethesda, Maryland, 20814, United States
2.	Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis St., #02-01 Genome, 138672, Singapore
3.	Department of Life Science & Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, China-Yi, Taiwan

Received September 2014 Revised March 2015 Published August 2015

Abstract
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We propose the hypothesis that for a particular type of cancer there exists a key pair of oncogene (OCG) and tumor suppressor gene (TSG) that is normally involved in strong stabilizing negative feedback loops (nFBLs) of molecular interactions, and it is these interactions that are sufficiently perturbed during cancer development. These nFBLs are thought to regulate oncogenic positive feedback loops (pFBLs) that are often required for the normal cellular functions of oncogenes. Examples given in this paper are the pairs of MYC and p53, KRAS and INK4A, and E2F1 and miR-17-92. We propose dynamical models of the aforementioned OCG-TSG interactions and derive stability conditions of the steady states in terms of strengths of cycles in the qualitative interaction network. Although these conditions are restricted to predictions of local stability, their simple linear expressions in terms of competing nFBLs and pFBLs make them intuitive and practical guides for experimentalists aiming to discover drug targets and stabilize cancer networks.

Keywords: p53, kras, miR-17-92, drug targets., ink4a, feedback loops, network stability, e2f1, cycle strength, myc, Oncogene-tumor suppressor gene pairs.

Mathematics Subject Classification: Primary: 92B05, 92C42; Secondary: 34C2.

Citation: Baltazar D. Aguda, Ricardo C.H. del Rosario, Michael W.Y. Chan. Oncogene-tumor suppressor gene feedback interactions and their control. Mathematical Biosciences & Engineering, 2015, 12 (6) : 1277-1288. doi: 10.3934/mbe.2015.12.1277

References:

[1]	B. D. Aguda, Network pharmacology of glioblastoma, Curr Drug Discov Technol., 10 (2013), 125-138.
[2]	B. D. Aguda, The significance of the feedback loops between KRas and Ink4a in pancreatic cancer, in Molecular Diagnostics and Therapy of Pancreatic Cancer (ed. A. Azmi), Elsevier Academic Press, (2014), 281-296. doi: 10.1016/B978-0-12-408103-1.00012-1.
[3]	B. D. Aguda and A. B. Goryachev, From pathways databases to network models of switching behavior, PLoS Comput Biol., 3 (2007), 1674-1678. doi: 10.1371/journal.pcbi.0030152.
[4]	B. D. Aguda, Y. Kim, H. S. Kim, A. Friedman and H. A. Fine, Qualitative network modeling of the Myc-p53 control system of cell proliferation and differentiation, Biophys J., 101 (2011), 2082-2091. doi: 10.1016/j.bpj.2011.09.052.
[5]	B. D. Aguda, Y. Kim, M. G. Piper-Hunter, A. Friedman and C. B. Marsh, MicroRNA regulation of a cancer network: Consequences of the feedback loops involving miR-17-92, E2F and Myc, Proc Natl Acad Sci USA, 105 (2008), 19678-19683. doi: 10.1073/pnas.0811166106.
[6]	R. C. Bast, B. Henessy and G. B. Mills, Jr., The biology of ovarian cancer: New opportunities for translation, Nat Rev Cancer, 9 (2009), 415-428.
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[8]	Cancer Genome Atlas Research Network, Comprehensive molecular profiling of lung adenocarcinoma, Nature, 511 (2014), 543-550.
[9]	W. A. Cooper, D. C. Lam, S. A. O'Toole and J. D. Minna, Molecular biology of lung cancer, J Thorac Dis., 5 (2013), S479-S490.
[10]	J. Daniluk, Y. Liu, D. Deng, J. Chu, H. Huang, S. Gaiser, Z. Cruz-Monserrate, H. Wang, B. Ji and C. D. Logsdon, An NF-$\kappa$B pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice, J Clin Invest., 122 (2012), 1519-1528.
[11]	A. Dhooge, W. Govaerts and Y. A. Kuznetsov, MATCONT: A Matlab package for numerical bifurcation analysis of ODEs, ACM Trans Math Softw (TOMS), 29 (2003), 141-164. doi: 10.1145/779359.779362.
[12]	J. Drost and R. Agami, Transformation locked in a loop, Cell, 139 (2009), 654-656. doi: 10.1016/j.cell.2009.10.035.
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[14]	P. K. Ha, S. S. Chang, C. A. Glazer, J. A. Califano and D. Sidransky, Molecular techniques and genetic alterations in head and neck cancer, Oral Oncol, 45 (2009), 335-339. doi: 10.1016/j.oraloncology.2008.05.015.
[15]	http://cancer.sanger.ac.uk/cancergenome/projects/census/
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[17]	C. Kandoth, M. D. McLellan, F. Vandin, K. Ye, B. Niu, C. Lu, M. Xie, Q. Zhang, J. F. McMichael, M. A. Wyczalkowski, M. D. Leiserson, C. A. Miller, J. S. Welch, M. J. Walter, M. C. Wendl, T. J. Ley, R. K. Wilson, B. J. Raphael and L. Ding, Mutational landscape and significance across 12 major cancer types, Nature, 502 (2013), 333-339.
[18]	J. E. Larsen and J. D. Minna, Molecular biology of lung cancer: Clinical applications, Clin Chest Med., 32 (2011), 703-740. doi: 10.1016/j.ccm.2011.08.003.
[19]	E. Y. Lee and W. J. Muller, Oncogenes and tumor suppressor genes, Cold Spring Harb Perpect Biol., 2 (2010), a003236. doi: 10.1101/cshperspect.a003236.
[20]	Y. Li, Y. Li, H. Zhang and Y. Chen, MicroRNA-mediated positive feedback loop and optimized bistable switch in a cancer network involving miR-17-92, PLoS One, 6 (2011), e26302. doi: 10.1371/journal.pone.0026302.
[21]	P. Liao, W. Wang, M. Shen, W. Pan, K. Zhang, R. Wang, T. Chen, Y. Chen, H. Chen and P. Wang, A positive feedback loop between EBP2 and c-Myc regulates rDNA transcription, cell proliferation, and tumorigenesis, Cell Death Dis., 5 (2014), e1032. doi: 10.1038/cddis.2013.536.
[22]	L. Mao, W. K. Hong and V. A. Papadimitrakopoulou, Focus on head and neck cancer, Cancer Cell, 5 (2004), 311-316. doi: 10.1016/S1535-6108(04)00090-X.
[23]	G. M. Marshall, P. Y. Liu, S. Gherardi, C. J. Scarlett, A. Bedalov, N. Xu, N. Iraci, E. Valli, D. Ling, W. Thomas, M. van Bekkum, E. Sekyere, K. Jankowski, T. Trahair, K. L. Mackenzie, M. Haber, M. D. Norris, A. V. Biankin, G. Perini and T. Liu, SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability, PLoS Genet., 7 (2011), e1002135. doi: 10.1371/journal.pgen.1002135.
[24]	K. Nowak, K. Kerl, D. Fehr, C. Kramps, C. Gessner, K. Killmer, B. Samans, B. Berwanger, H. Christiansen and W. Lutz, BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas, Nucleic Acids Res., 34 (2006), 1745-1754. doi: 10.1093/nar/gkl119.
[25]	B. Perez-Ordoñez, M. Beauchemin and R. C. Jordan, Molecular biology of squamous cell carcinoma of the head and neck, J Clin Pathol., 59 (2006), 445-4453.
[26]	C. C. Pritchard and W. M. Grady, Colorectal cancer molecular biology moves into clinical practice, Gut., 60 (2011), 116-129. doi: 10.1136/gut.2009.206250.
[27]	T. Santarius, J. Shipley, D. Brewer, M. R. Stratton and C. S. Cooper, A census of amplified and overexpressed human cancer genes, Nat Rev Cancer, 10 (2010), 59-64. doi: 10.1038/nrc2771.
[28]	K. Tago, M. Funakoshi-Tago, H. Itoh, Y. Furukawa, J. Kikuchi, T. Kato, K. Suzuki and K. Yanagisawa, Arf tumor suppressor disrupts the oncogenic positive feedback loop including c-Myc and DDX5, Oncogene, 34 (2015), 314-322. doi: 10.1038/onc.2013.561.
[29]	P. Takahashi, A. Polson and D. Reisman, Elevated transcription of the p53 gene in early S-phase leads to a rapid DNA-damage response during S-phase of the cell cycle, Apoptosis, 16 (2011), 950-958. doi: 10.1007/s10495-011-0623-z.
[30]	D. Tamborero, A. Gonzalez-Perez, C. Perez-Llamas, J. Deu-Pons, C. Kandoth, J. Reimand, M. S. Lawrence, G. Getz, G. D. Bader, L. Ding and N. Lopez-Bigas, Comprehensive identification of mutational cancer driver genes across 12 tumor types, Sci Rep., 3 (2013), p2650. doi: 10.1038/srep02650.
[31]	M. Vauhkonen, H. Vauhkonen and P. Sipponen, Pathology and molecular biology of gastric cancer, Best Pract Res Clin Gastroenterol, 20 (2006), 651-674. doi: 10.1016/j.bpg.2006.03.016.

show all references

References:

[1]	B. D. Aguda, Network pharmacology of glioblastoma, Curr Drug Discov Technol., 10 (2013), 125-138.
[2]	B. D. Aguda, The significance of the feedback loops between KRas and Ink4a in pancreatic cancer, in Molecular Diagnostics and Therapy of Pancreatic Cancer (ed. A. Azmi), Elsevier Academic Press, (2014), 281-296. doi: 10.1016/B978-0-12-408103-1.00012-1.
[3]	B. D. Aguda and A. B. Goryachev, From pathways databases to network models of switching behavior, PLoS Comput Biol., 3 (2007), 1674-1678. doi: 10.1371/journal.pcbi.0030152.
[4]	B. D. Aguda, Y. Kim, H. S. Kim, A. Friedman and H. A. Fine, Qualitative network modeling of the Myc-p53 control system of cell proliferation and differentiation, Biophys J., 101 (2011), 2082-2091. doi: 10.1016/j.bpj.2011.09.052.
[5]	B. D. Aguda, Y. Kim, M. G. Piper-Hunter, A. Friedman and C. B. Marsh, MicroRNA regulation of a cancer network: Consequences of the feedback loops involving miR-17-92, E2F and Myc, Proc Natl Acad Sci USA, 105 (2008), 19678-19683. doi: 10.1073/pnas.0811166106.
[6]	R. C. Bast, B. Henessy and G. B. Mills, Jr., The biology of ovarian cancer: New opportunities for translation, Nat Rev Cancer, 9 (2009), 415-428.
[7]	Cancer Genome Atlas Research Network, Comprehensive genomic characterization defines human glioblastoma genes and core pathways, Nature, 494 (2013), p506. doi: 10.1038/nature11903.
[8]	Cancer Genome Atlas Research Network, Comprehensive molecular profiling of lung adenocarcinoma, Nature, 511 (2014), 543-550.
[9]	W. A. Cooper, D. C. Lam, S. A. O'Toole and J. D. Minna, Molecular biology of lung cancer, J Thorac Dis., 5 (2013), S479-S490.
[10]	J. Daniluk, Y. Liu, D. Deng, J. Chu, H. Huang, S. Gaiser, Z. Cruz-Monserrate, H. Wang, B. Ji and C. D. Logsdon, An NF-$\kappa$B pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice, J Clin Invest., 122 (2012), 1519-1528.
[11]	A. Dhooge, W. Govaerts and Y. A. Kuznetsov, MATCONT: A Matlab package for numerical bifurcation analysis of ODEs, ACM Trans Math Softw (TOMS), 29 (2003), 141-164. doi: 10.1145/779359.779362.
[12]	J. Drost and R. Agami, Transformation locked in a loop, Cell, 139 (2009), 654-656. doi: 10.1016/j.cell.2009.10.035.
[13]	P. A. Futreal, L. Coin, M. Marshall, T. Down, T. Hubbard, R. Wooster, N. Rahman and M. R. Stratton, A census of human cancer genes, Nat Rev Cancer, 4 (2004), 177-183. doi: 10.1038/nrc1299.
[14]	P. K. Ha, S. S. Chang, C. A. Glazer, J. A. Califano and D. Sidransky, Molecular techniques and genetic alterations in head and neck cancer, Oral Oncol, 45 (2009), 335-339. doi: 10.1016/j.oraloncology.2008.05.015.
[15]	http://cancer.sanger.ac.uk/cancergenome/projects/census/
[16]	http://ncg.kcl.ac.uk (network of cancer genes).
[17]	C. Kandoth, M. D. McLellan, F. Vandin, K. Ye, B. Niu, C. Lu, M. Xie, Q. Zhang, J. F. McMichael, M. A. Wyczalkowski, M. D. Leiserson, C. A. Miller, J. S. Welch, M. J. Walter, M. C. Wendl, T. J. Ley, R. K. Wilson, B. J. Raphael and L. Ding, Mutational landscape and significance across 12 major cancer types, Nature, 502 (2013), 333-339.
[18]	J. E. Larsen and J. D. Minna, Molecular biology of lung cancer: Clinical applications, Clin Chest Med., 32 (2011), 703-740. doi: 10.1016/j.ccm.2011.08.003.
[19]	E. Y. Lee and W. J. Muller, Oncogenes and tumor suppressor genes, Cold Spring Harb Perpect Biol., 2 (2010), a003236. doi: 10.1101/cshperspect.a003236.
[20]	Y. Li, Y. Li, H. Zhang and Y. Chen, MicroRNA-mediated positive feedback loop and optimized bistable switch in a cancer network involving miR-17-92, PLoS One, 6 (2011), e26302. doi: 10.1371/journal.pone.0026302.
[21]	P. Liao, W. Wang, M. Shen, W. Pan, K. Zhang, R. Wang, T. Chen, Y. Chen, H. Chen and P. Wang, A positive feedback loop between EBP2 and c-Myc regulates rDNA transcription, cell proliferation, and tumorigenesis, Cell Death Dis., 5 (2014), e1032. doi: 10.1038/cddis.2013.536.
[22]	L. Mao, W. K. Hong and V. A. Papadimitrakopoulou, Focus on head and neck cancer, Cancer Cell, 5 (2004), 311-316. doi: 10.1016/S1535-6108(04)00090-X.
[23]	G. M. Marshall, P. Y. Liu, S. Gherardi, C. J. Scarlett, A. Bedalov, N. Xu, N. Iraci, E. Valli, D. Ling, W. Thomas, M. van Bekkum, E. Sekyere, K. Jankowski, T. Trahair, K. L. Mackenzie, M. Haber, M. D. Norris, A. V. Biankin, G. Perini and T. Liu, SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability, PLoS Genet., 7 (2011), e1002135. doi: 10.1371/journal.pgen.1002135.
[24]	K. Nowak, K. Kerl, D. Fehr, C. Kramps, C. Gessner, K. Killmer, B. Samans, B. Berwanger, H. Christiansen and W. Lutz, BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas, Nucleic Acids Res., 34 (2006), 1745-1754. doi: 10.1093/nar/gkl119.
[25]	B. Perez-Ordoñez, M. Beauchemin and R. C. Jordan, Molecular biology of squamous cell carcinoma of the head and neck, J Clin Pathol., 59 (2006), 445-4453.
[26]	C. C. Pritchard and W. M. Grady, Colorectal cancer molecular biology moves into clinical practice, Gut., 60 (2011), 116-129. doi: 10.1136/gut.2009.206250.
[27]	T. Santarius, J. Shipley, D. Brewer, M. R. Stratton and C. S. Cooper, A census of amplified and overexpressed human cancer genes, Nat Rev Cancer, 10 (2010), 59-64. doi: 10.1038/nrc2771.
[28]	K. Tago, M. Funakoshi-Tago, H. Itoh, Y. Furukawa, J. Kikuchi, T. Kato, K. Suzuki and K. Yanagisawa, Arf tumor suppressor disrupts the oncogenic positive feedback loop including c-Myc and DDX5, Oncogene, 34 (2015), 314-322. doi: 10.1038/onc.2013.561.
[29]	P. Takahashi, A. Polson and D. Reisman, Elevated transcription of the p53 gene in early S-phase leads to a rapid DNA-damage response during S-phase of the cell cycle, Apoptosis, 16 (2011), 950-958. doi: 10.1007/s10495-011-0623-z.
[30]	D. Tamborero, A. Gonzalez-Perez, C. Perez-Llamas, J. Deu-Pons, C. Kandoth, J. Reimand, M. S. Lawrence, G. Getz, G. D. Bader, L. Ding and N. Lopez-Bigas, Comprehensive identification of mutational cancer driver genes across 12 tumor types, Sci Rep., 3 (2013), p2650. doi: 10.1038/srep02650.
[31]	M. Vauhkonen, H. Vauhkonen and P. Sipponen, Pathology and molecular biology of gastric cancer, Best Pract Res Clin Gastroenterol, 20 (2006), 651-674. doi: 10.1016/j.bpg.2006.03.016.

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