Korean J Gastroenterol.  2011 Jan;57(1):3-7. 10.4166/kjg.2011.57.1.3.

The Role of NF-kappaB in Colon Cancer

• Seo GS

• KMID: 991461
• DOI: http://doi.org/10.4166/kjg.2011.57.1.3

Abstract

Colon cancer is the 3rd common malignancy and 4th common cause of cancer death in Korea. Recent studies have shown that abnormal inflammatory response plays a critical role in colon carcinogenesis. A striking example of connection between inflammation and cancer is NF-kappaB, in which key regulator of inflammation and immune response is associated with target for colon cancer treatment. Constitutive NF-kappaB expression in colon cancer is 40-80% in vivo as well as in vitro, and the inactivation of IKKbeta subunit can reduce tumor multiplicity. The possible mechanisms by which NF-kappaB can contribute to colon carcinogenesis include the activator of antiapoptotic gene expression, enhanced cell survival and proliferation, regulation of angiogenesis and promotion of metastasis of cancer cells. Recent insights into the role of NF-kappaB involved in colon cancer development as well as their relevance as therapeutic targets are herein discussed.

Keyword

NF-kappaB; Colon cancer; IKKbeta; Inflammation

MeSH Terms

Colonic Neoplasms/*etiology/metabolism
Humans
I-kappa B Kinase/metabolism/physiology
Inflammation
NF-kappa B/metabolism/*physiology

Figure

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  Fig. 1. NF-κ B signaling pathways.

Reference

References

1. Koh SJ, Kim JS. The reasons for the increased incidence of colorectal cancer in Korea. Korean J Med. 2010; 79:97–103.

2. Tenesa A, Dunlop MG. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet. 2009; 10:353–358.

3. Rustgi AK. The genetics of hereditary colon cancer. Genes Dev. 2007; 21:2525–2538.

4. Terzić J, Grivennikov S, Karin E, Karin M. Inflammation and colon cancer. Gastroenterology. 2010; 138:2101–2114.

5. Lee SH, Hu LL, Gonzalez-Navajas J, et al. ERK activation drives intestinal tumorigenesis in Apc (min/+) mice. Nat Med. 2010; 16:665–670.

6. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008; 454:436–444.

7. Kundu JK, Surh YJ. Inflammation: gearing the journey to cancer. Mutat Res. 2008; 659:15–30.

8. Baud V, Karin M. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov. 2009; 8:33–40.

9. Burstein E, Fearon ER. Colitis and cancer: a tale of inflammatory cells and their cytokines. J Clin Invest. 2008; 118:464–467.

10. Lind DS, Hochwald SN, Malaty J, et al. Nuclear factor-κ B is upregulated in colorectal cancer. Surgery. 2001; 130:363–369.

11. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-κ B. Nature. 1997; 388:548–554.

12. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a metaanalysis. Gut. 2001; 48:526–535.

13. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. 1990; 323:1228–1233.

14. Gyde SN, Prior P, Macartney JC, Thompson H, Waterhouse JA, Allan RN. Malignancy in Crohn's disease. Gut. 1980; 21:1024–1029.

15. Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer. 2001; 91:854–862.

16. Canavan C, Abrams KR, Mayberry J. Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease. Aliment Pharmacol Ther. 2006; 23:1097–1104.

17. Freeman HJ. Colorectal cancer risk in Crohn's disease. World J Gastroenterol. 2008; 14:1810–1811.

18. Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer. 2001; 91:854–862.

19. Atreya I, Atreya R, Neurath MF. NF-κ B in inflammatory bowel disease. J Intern Med. 2008; 263:591–596.

20. Rogler G, Brand K, Vogl D, et al. Nuclear factor κ B is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology. 1998; 115:357–369.

21. Neurath MF, Fuss I, Schürmann G, et al. Cytokine gene transcription by NF-κ B family members in patients with inflammatory bowel disease. Ann NY Acad Sci. 1998; 859:149–159.

22. Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther. 2003; 18(Suppl 2):1–5.

23. Yan F, Polk DB. Aminosalicylic acid inhibits IkB kinase alpha phosphorylation of Iκ B alpha in mouse intestinal epithelial cells. J Biol Chem. 1999; 274:36631–36636.

24. Greten FR, Eckmann L, Greten TF, et al. IKK beta links inflammation and tumorigenesis in amouse model of colitis-associated cancer. Cell. 2004; 118:285–296.

25. Shibata W, Maeda S, Hikiba Y, et al. Cutting edge: the Iκ B kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks inflammatory injury in murine colitis. J Immunol. 2007; 179:2681–2685.

26. Karin M, Cao Y, Greten FR, Li ZW. NFκ B in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002; 2:301–310.

27. Horst D, Budczies J, Brabletz T, Kirchner T, Hlubek F. Invasion associated upregulation of nuclear factor kappaB target genes in colorectal cancer. Cancer. 2009; 115:4946–4958.

28. Sakamoto K, Maeda S, Hikiba Y, et al. Constitutive NFκ B activation in colorectal carcinoma plays a key role in angiogenesis, promoting tumor growth. Clin Cancer Res. 2009; 15:2248–2258.

29. Luo JL, Kamata H, Karin M. IKK/NFκ B signaling: balancing life and death–a new approach to cancer therapy. J Clin Invest. 2005; 115:2625–2632.

30. Joyce D, Albanese C, Steer J, Fu M, Bouzahzah B, Pestell RG. NFκ B and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev. 2001; 12:73–90.

31. Hanada T, Yoshimura A. Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev. 2002; 13:413–421.

32. Goldring MB, Otero M, Tsuchimochi K, Ijiri K, Li Y. Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism. Ann Rheum Dis. 2008; 67(Suppl 3):iii75–82.

33. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link? Biochem Pharmacol. 2006; 72:1605–1621.

34. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002; 2:161–174.

35. Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009; 28:15–33.

36. Huber MA, Azoitei N, Baumann B, et al. NFκ B is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004; 114:569–581.

37. Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP. Stabilization of snail by NFκ B is required for inflammation-induced cell migration and invasion. Cancer Cell. 2009; 15:416–428.

38. Caponigro F, Lacombe D, Twelves C, et al. An EORTC phase I study of Bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer. Eur J Cancer. 2009; 45:48–55.

39. Singhal S, Mehta J. Thalidomide in cancer: potential uses and limitations. BioDrugs. 2001; 15:163–172.

40. Subbarayan PR, Lima M, Ardalan B. Arsenic triox-ide/ascorbic acid therapy in patients with refractory metastatic colorectal carcinoma: a clinical experience. Acta Oncol. 2007; 46:557–561.

41. Kemeny N, Capanu M, D'Angelica M, et al. Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxur-idine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer. Ann Oncol. 2009; 20:1236–1241.

42. Sakamoto K, Maeda S. Targeting NF-kappaB for colorectal cancer. Expert Opin Ther Targets. 2010; 14:593–601.