Skip to main content
Log in

Network-based approach to understand dynamic behaviour of Wnt signaling pathway regulatory elements in colorectal cancer

  • Original Article
  • Published:
Network Modeling Analysis in Health Informatics and Bioinformatics Aims and scope Submit manuscript

Abstract

Systems biology helps to understand the intricate biological processes through the regulatory and metabolic mechanism. Modeling and simulation are the computational approaches to encounter the physiological and disease processes by means of an artificial environment that precisely mimics the conditions inside the cell. A large proportion of colorectal cancers (CRC) display mutational inactivation of the variety of pathways and Wnt-signaling is thought to be one of the major contributors from all the pathways that show progression towards CRC. In our study, we have performed a computational analysis to envisage the role of candidate genes for the Wnt signaling pathway. Quantitative simulations have been performed for the colorectal carcinoma. In addition, network motifs detection was performed so as to decipher the role of crucial components in the pathophysiology of CRC. Based on the standard statistical parameters such as Z score, p value and significance profile candidate genes were recovered from the Wnt pathway. The proposed method revealed statistical significance of five key genes i.e. Axin, APC, β-catenin, Lef1, and Myc reflecting their importance to study disease condition. These genes could prove to be efficient markers for the disease diagnosis and also provide a way to solve the mystery behind the aberrant regulation of Wnt signaling in CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Alon U (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8:450–461. https://doi.org/10.1038/nrg2102

    Article  Google Scholar 

  • Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F (2016) Global patterns and trends in colorectal cancer incidence and mortality. Gut. https://doi.org/10.1136/gutjnl-2015-310912

    Article  Google Scholar 

  • Barabási A-L, Gulbahce N, Loscalzo J (2011) Network medicine: a network-based approach to human disease. Nat Rev Genet 12:56–68

    Article  Google Scholar 

  • Chelliah V, Laibe C, Le Novère N (2013) BioModels database: a repository of mathematical models of biological processes. In: Encyclopedia of systems biology. Springer, New York, NY, pp 134–138

    Chapter  Google Scholar 

  • Cho KH, Baek S, Sung MH (2006) Wnt pathway mutations selected by optimal beta-catenin signaling for tumorigenesis. FEBS Lett 580:3665–3670. https://doi.org/10.1016/j.febslet.2006.05.053

    Article  Google Scholar 

  • Dietlein F, Thelen L, Reinhardt HC (2014) Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches. Trends Genet 30:326–339

    Article  Google Scholar 

  • Dormand JR, Prince PJ (1980) A family of embedded Runge–Kutta formulae. J Comput Appl Math 6:19–26

    Article  MathSciNet  Google Scholar 

  • Drager A, Hassis N, Supper J, Schroder A, Zell A (2008) SBMLsqueezer: a CellDesigner plug-in to generate kinetic rate equations for biochemical networks. BMC Syst Biol 2:39. https://doi.org/10.1186/1752-0509-2-39

    Article  Google Scholar 

  • Gavande NS, VanderVere-Carozza PS, Hinshaw HD, Jalal SI, Sears CR, Pawelczak KS, Turchi JJ (2016) DNA repair targeted therapy: the past or future of cancer treatment? Pharmacol Ther 160:65–83. https://doi.org/10.1016/j.pharmthera.2016.02.003

    Article  Google Scholar 

  • Goldbeter A, Pourquié O (2008) Modeling the segmentation clock as a network of coupled oscillations in the Notch, Wnt and FGF signaling pathways. J Theor Biol 252:574–585

    Article  MathSciNet  Google Scholar 

  • Grady WM, Markowitz SD (2002) Genetic and epigenetic alterations in colon cancer. Ann Rev Genom Hum Genet 3:101–128

    Article  Google Scholar 

  • Haggar FA, Boushey RP (2009) Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 22:191–197 https://doi.org/10.1055/s-0029-1242458

    Article  Google Scholar 

  • Hisamuddin IM, Yang VW (2006) Molecular genetics of colorectal cancer: an overview. Curr Colorectal Cancer Rep 2:53–59

    Article  Google Scholar 

  • Hochman G, Halevi-Tobias K, Kogan Y, Agur Z (2017) Extracellular inhibitors can attenuate tumorigenic Wnt pathway activity in adenomatous polyposis coli mutants: predictions of a validated mathematical model. PloS One 12:e0179888

    Article  Google Scholar 

  • Huang MY et al (2013) Significant overexpression of DVL1 in Taiwanese colorectal cancer patients with liver metastasis. Int J Mol Sci 14:20492–20507. https://doi.org/10.3390/ijms141020492

    Article  Google Scholar 

  • Kanehisa M (2002) The KEGG database. Novartis Found Symp 247:91–101 (discussion 101–103, 119–128, 244–252)

    Article  Google Scholar 

  • Katoh M (2007) Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis. Stem Cell Rev 3:30–38

    Article  Google Scholar 

  • Kestler HA, Kuhl M (2008) From individual Wnt pathways towards a Wnt signalling network philosophical transactions of the Royal Society of London Series B. Biol Sci 363:1333–1347. https://doi.org/10.1098/rstb.2007.2251

    Article  Google Scholar 

  • Kruger R, Heinrich R (2004) Model reduction and analysis of robustness for the Wnt/beta-catenin signal transduction pathway. Genome Inf Int Conf Genome Inf 15:138–148

    Google Scholar 

  • Lee E, Salic A, Kruger R, Heinrich R, Kirschner MW (2003) The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol 1:E10. https://doi.org/10.1371/journal.pbio.0000010

    Article  Google Scholar 

  • Li SK, Martin A (2016) Mismatch repair and colon cancer: mechanisms and therapies explored. Trends Mol Med 22:274–289

    Article  Google Scholar 

  • MacLean AL, Harrington HA, Stumpf MP, Byrne HM (2016) Mathematical and statistical techniques for systems medicine: the Wnt signaling pathway as a case study. Systems medicine. Humana Press, New York, 405–439

    Google Scholar 

  • Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361:2449–2460. https://doi.org/10.1056/NEJMra0804588

    Article  Google Scholar 

  • Martin GS (2003) Cell signaling cancer. Cancer Cell 4:167–174

    Article  Google Scholar 

  • MathWorks T (2012) MATLAB and statistics toolbox release 2012a. The MathWorks, Inc, Natick

    Google Scholar 

  • Mirams GR, Byrne HM, King JR (2010) A multiple timescale analysis of a mathematical model of the Wnt/β-catenin signalling pathway. J Math Biol 60:131–160

    Article  MathSciNet  Google Scholar 

  • Peltomaki P (2001) Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet 10:735–740

    Article  Google Scholar 

  • Saha S, Roman T, Galante A, Koyuturk M, Ewing RM (2012) Network-based approaches for extending the Wnt signalling pathway and identifying context-specific sub-networks. Int J Comput Biol Drug Des 5:185–205. https://doi.org/10.1504/IJCBDD.2012.049203

    Article  Google Scholar 

  • Schneikert J, Behrens J (2007) The canonical Wnt signalling pathway and its APC partner in colon cancer development. Gut 56:417–425. https://doi.org/10.1136/gut.2006.093310

    Article  Google Scholar 

  • Shukla A, Sehgal M, Singh TR (2015) Hydroxymethylation and its potential implication in DNA repair system: a review and future perspectives. Gene 564:109–118. https://doi.org/10.1016/j.gene.2015.03.075

    Article  Google Scholar 

  • Shukla A, Moussa A, Singh TR (2016) DREMECELS: a curated database for base excision and mismatch repair mechanisms associated human malignancies. PloS One 11:e0157031. https://doi.org/10.1371/journal.pone.0157031

    Article  Google Scholar 

  • Shukla A, Yennamalli RM, Singh TR (2018) Network and structure based inference of functional single nucleotide polymorphisms associated with the TGFβ1 gene and its role in colorectal cancer (CRC). Gene Rep 11:131–142

    Article  Google Scholar 

  • Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S (2011) A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways. Omics J Integr Biol 15:729–737

    Article  Google Scholar 

  • Smaglo BG, Marshall JL (2013) Microsatellite instability in colorectal cancer. Clin Adv Hematol Oncol H&O 11:659–661

    Google Scholar 

  • Tan CW, Gardiner BS, Hirokawa Y, Layton MJ, Smith DW, Burgess AW (2012) Wnt signalling pathway parameters for mammalian cells. PloS One 7:e31882. https://doi.org/10.1371/journal.pone.0031882

    Article  Google Scholar 

  • Tariq K, Ghias K (2016) Colorectal cancer carcinogenesis: a review of mechanisms. Cancer Biol Med 13:120–135. https://doi.org/10.28092/j.issn.2095-3941.2015.0103

    Article  Google Scholar 

  • van Leeuwen IM, Byrne HM, Jensen OE, King JR (2007) Elucidating the interactions between the adhesive and transcriptional functions of β-catenin in normal and cancerous cells. J Theor Biol 247:77–102

    Article  MathSciNet  Google Scholar 

  • Wernicke S, Rasche F (2006) FANMOD: a tool for fast network motif detection. Bioinformatics 22:1152–1153

    Article  Google Scholar 

  • Young MA, Daly CS, Taylor E, James R, Clarke AR, Reed KR (2018) Subtle deregulation of the Wnt-signaling pathway through loss of Apc2 reduces the fitness of intestinal stem cells. Stem Cells 36:114–122

    Article  Google Scholar 

  • Zeng ZS, Shu WP, Cohen AM, Guillem JG (2002) Matrix metalloproteinase-7 expression in colorectal cancer liver metastases: evidence for involvement of MMP-7 activation in human cancer metastases. Clin Cancer Res 8:144–148

    Google Scholar 

  • Zhang W et al (2015) Upregulation of nemo-like kinase is an independent prognostic factor in colorectal cancer. World J Gastroenterol WJG 21:8836

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tiratha Raj Singh.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

13721_2018_175_MOESM1_ESM.png

Supplementary Fig 1. Simulation run for all set of entities included in the Wnt pathway signaling. The graph shows the dynamic behavior of the set of Wnt proteins when considered at certain amount (concentration) and time period (PNG 356 KB)

Supplementary material 2 (DOCX 16 KB)

Supplementary material 3 (XLSX 79 KB)

Supplementary material 4 (DOCX 15 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shukla, A., Singh, T.R. Network-based approach to understand dynamic behaviour of Wnt signaling pathway regulatory elements in colorectal cancer. Netw Model Anal Health Inform Bioinforma 7, 14 (2018). https://doi.org/10.1007/s13721-018-0175-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13721-018-0175-z

Keywords

Navigation