Tumor Biology

, 32:1005 | Cite as

Differential expression of TNF-α signaling molecules and ERK1 in distal and proximal colonic tumors associated with obesity

  • Swati S. Jain
  • Manickaraj AshokKumar
  • Ranjana P. Bird
Research Article

Abstract

Distal and proximal colon cancers have been recognized as two different disease types in human population. The environmental factors involved in the pathogenesis of the proximal and distal tumors also differ. The main objective of this study was to determine if obesity-augmented colonic tumors differ from each other if they are located in different regions of the colonic axis. Zucker obese rats were injected with azoxymethane (AOM) 10 mg/kg body weight/week for 2 weeks. The tumors appeared within 20 weeks. The highest proportion of the tumors was in the distal colon, and the number declined towards the splenic flexure. A number of proteins previously reported to be altered in tumor tissue were assessed in the present study in tumors appearing in proximal and distal regions. Distal colonic tumors had higher TNF-α R2, NF-κB, and IκBα levels than tumors of proximal origin. In contrast, IKKβ was decreased in the proximal tumors. Insulin receptor and insulin-like growth factor-1R were higher in distal tumors. The mitogen-activated protein kinase (ERK2) levels were similar in the tumor groups; however, the ERK1 was significantly higher in the distal tumor than in the proximal tumor. Our findings suggest that colon tumors induced by AOM in different colonic regions are different from each other with respect to differential expression of proteins and support the concept that these disease states could respond differently to tumor-promoting and inhibitory conditions. Moreover, these findings support the concept that cancer preventive or therapeutic agents need to be evaluated for their effectiveness on proximal as well as on distal tumors.

Keywords

Colon cancer Distal and proximal Obesity Zucker rats Azoxymethane 

Notes

Acknowledgments

The research was supported by the Discovery Grant Natural Sciences and Engineering Council of Canada and in part by the Cancer Research Society Inc. Canada to RPB.

Conflicts of interest

None

References

  1. 1.
    Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer. 2002;101(5):403–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Distler P, Holt PR. Are right- and left-sided colon neoplasms distinct tumors? Dig Dis. 1997;15(4–5):302–11.PubMedCrossRefGoogle Scholar
  3. 3.
    Saif MW, Chu E. Biology of colorectal cancer. Cancer J. 2010;16(3):196–201.PubMedCrossRefGoogle Scholar
  4. 4.
    Yamamoto M, Mine H, Kusumoto H, Maehara Y, Sugimachi K. Polyps with different grades of dysplasia and their distribution in the colorectum. Hepatogastroenterology. 2004;51(55):121–3.PubMedGoogle Scholar
  5. 5.
    Gervaz P, Bucher P, Neyroud-Caspar I, Soravia C, Morel P. Proximal location of colon cancer is a risk factor for development of metachronous colorectal cancer: a population-based study. Dis Colon Rectum. 2005;48(2):227–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Azzoni C, Bottarelli L, Campanini N, Di Cola G, Bader G, Mazzeo A, et al. Distinct molecular patterns based on proximal and distal sporadic colorectal cancer: arguments for different mechanisms in the tumorigenesis. Int J Colorectal Dis. 2007;22(2):115–26.PubMedCrossRefGoogle Scholar
  7. 7.
    Lindblom A. Different mechanisms in the tumorigenesis of proximal and distal colon cancers. Curr Opin Oncol. 2001;13(1):63–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med. 1990;113(10):779–88.PubMedGoogle Scholar
  9. 9.
    Gunter MJ, Leitzmann MF. Obesity and colorectal cancer: epidemiology, mechanisms and candidate genes. J Nutr Biochem. 2006;17(3):145–56.PubMedCrossRefGoogle Scholar
  10. 10.
    Shinchi K, Kono S, Honjo S, Todoroki I, Sakurai Y, Imanishi K, et al. Obesity and adenomatous polyps of the sigmoid colon. Jpn J Cancer Res. 1994;85(5):479–84.PubMedGoogle Scholar
  11. 11.
    Dai Z, Xu YC, Niu L. Obesity and colorectal cancer risk: a meta-analysis of cohort studies. World J Gastroenterol. 2007;13(31):4199–206.PubMedGoogle Scholar
  12. 12.
    Slattery ML, Wolff E, Hoffman MD, Pellatt DF, Milash B, Wolff RK. MicroRNAs and colon and rectal cancer: differential expression by tumor location and subtype. Genes Chromosomes Cancer. 2011;50(3):196–206.PubMedCrossRefGoogle Scholar
  13. 13.
    Minoo P, Zlobec I, Peterson M, Terracciano L, Lugli A. Characterization of rectal, proximal and distal colon cancers based on clinicopathological, molecular and protein profiles. Int J Oncol. 2010;37(3):707–18.PubMedCrossRefGoogle Scholar
  14. 14.
    Bird RP. Role of aberrant crypt foci in understanding the pathogenesis of colon cancer. Cancer Lett. 1995;93(1):55–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Jain SS, Bird RP. Elevated expression of tumor necrosis factor-α signaling molecules in colonic tumors of Zucker obese (fa/fa) rats. Int J Cancer. 2010;127(9):2042–50.PubMedCrossRefGoogle Scholar
  16. 16.
    Hilska M, Collan Y, Roberts PJ, Ovaska J, Kössi J, Paajanen H, et al. Prognostic value of various staging and grading systems in proximal colon cancer. Eur J Surg. 2002;168(2):84–90.PubMedCrossRefGoogle Scholar
  17. 17.
    Gaur U, Aggarwal BB. Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. Biochem Pharmacol. 2003;66(8):1403–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso G. NF-kappaB and JNK: an intricate affair. Cell Cycle. 2004;3(12):1524–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18:621–63.PubMedCrossRefGoogle Scholar
  20. 20.
    Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling: balancing life and death—a new approach to cancer therapy. J Clin Invest. 2005;115(10):2625–32.PubMedCrossRefGoogle Scholar
  21. 21.
    Remacle-Bonnet MM, Garrouste FL, Heller S, André F, Marvaldi JL, Pommier GJ. Insulin-like growth factor-I protects colon cancer cells from death factor-induced apoptosis by potentiating tumor necrosis factor alpha-induced mitogen-activated protein kinase and nuclear factor kappaB signaling pathways. Cancer Res. 2000;60(7):2007–17.PubMedGoogle Scholar
  22. 22.
    Kim EJ, Holthuizen PE, Kim J, Park JH. Overexpression of mature insulin-like growth factor (IGF)-II leads to growth arrest in Caco-2 human colon cancer cells. Growth Horm IGF Res. 2005;15(1):64–71.PubMedCrossRefGoogle Scholar
  23. 23.
    Alberobello AT, D'Esposito V, Marasco D, Doti N, Ruvo M, Bianco R, et al. Selective disruption of insulin-like growth factor-1 (IGF-1) signaling via phosphoinositide-dependent kinase-1 prevents the protective effect of IGF-1 on human cancer cell death. J Biol Chem. 2010;285(9):6563–72.PubMedCrossRefGoogle Scholar
  24. 24.
    Swede H, Rohan TE, Yu H, Anderson JC, Stevens RG, Brokaw J, et al. Number of aberrant crypt foci associated with adiposity and IGF1 bioavailability. Cancer Causes Control. 2009;20(5):653–61.PubMedCrossRefGoogle Scholar
  25. 25.
    Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoël MJ, Barbu V, Fartoux L, Poupon R, et al. Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer. 2006;119(11):2557–66.PubMedCrossRefGoogle Scholar
  26. 26.
    Milella M, Kornblau SM, Andreeff M. The mitogen-activated protein kinase signaling module as a therapeutic target in hematologic malignancies. Rev Clin Exp Hematol. 2003;7(2):160–90.PubMedGoogle Scholar
  27. 27.
    Adams JP, Sweatt JD. Molecular psychology: roles for the ERK MAP kinase cascade in memory. Annu Rev Pharmacol Toxicol. 2002;42:135–63.PubMedCrossRefGoogle Scholar
  28. 28.
    Lloyd AC. Distinct functions for ERKs? J Biol. 2006;5(5):13.PubMedCrossRefGoogle Scholar
  29. 29.
    Pagès G, Guérin S, Grall D, Bonino F, Smith A, Anjuere F, et al. Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science. 1999;286(5443):1374–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Hong SK, Yoon S, Moelling C, Arthan D, Park JI. Noncatalytic function of ERK1/2 can promote Raf/MEK/ERK-mediated growth arrest signaling. J Biol Chem. 2009;284(48):33006–18.PubMedCrossRefGoogle Scholar
  31. 31.
    Saba-El-Leil MK, Vella FD, Vernay B, Voisin L, Chen L, Labrecque N, et al. An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep. 2003;4(10):964–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Yao Y, Li W, Wu J, Germann UA, Su MS, Kuida K, et al. Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation. Proc Natl Acad Sci U S A. 2003;100(22):12759–64.PubMedCrossRefGoogle Scholar
  33. 33.
    Broadhurst (1999) The roles of protein kinases in the early and late stages of colon carcinogenesis. Dissertation, University of MannitobaGoogle Scholar
  34. 34.
    Lawrence MC, Jivan A, Shao C, Duan L, Goad D, Zaganjor E, et al. The roles of MAPKs in disease. Cell Res. 2008;18(4):436–42.PubMedCrossRefGoogle Scholar
  35. 35.
    Mladenova D, Daniel JJ, Dahlstrom JE, Bean E, Gupta R, Pickford R, et al. The NSAID sulindac is chemopreventive in the mouse distal colon but carcinogenic in the proximal colon. Gut. 2011;60(3):350–60.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2011

Authors and Affiliations

  • Swati S. Jain
    • 1
  • Manickaraj AshokKumar
    • 2
  • Ranjana P. Bird
    • 2
  1. 1.Department of Human Health and Nutritional SciencesUniversity of GuelphGuelphCanada
  2. 2.Department of Biological SciencesUniversity of WindsorWindsorCanada

Personalised recommendations