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1 Korean J Gastroenterol Vol. 57, No. 1, 3-7 DOI: /kjg REVIEW ARTICLE 대장암에서 NF-κB 의역할 서검석 원광대학교의과대학소화기내과학교실, 소화기질환연구소 The Role of NF-κB in Colon Cancer Geom Seog Seo Department of Internal Medicine, Digestive Disease Research Institute, Wonkwang University College of Medicine, Iksan, Korea Colon cancer is the 3 rd common malignancy and 4 th 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-κB, in which key regulator of inflammation and immune response is associated with target for colon cancer treatment. Constitutive NF-κB expression in colon cancer is 40-80% in vivo as well as in vitro, and the inactivation of IKKβ subunit can reduce tumor multiplicity. The possible mechanisms by which NF-κB 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-κB involved in colon cancer development as well as their relevance as therapeutic targets are herein discussed. (Korean J Gastroenterol 2011;57:3-7) Key Words: NF-κB; Colon cancer; IKKβ; Inflammation 서론 대장암은우리나라암발생비율중세번째를, 암으로인한사망중네번째 (12.8명/10만명) 를차지하고있고, 발생률도점차적으로증가하고있다. 1 전세계적으로도매년백만명의대장암환자가진단되며, 전체암의세번째, 사망원인의네번째를차지하고있다. 2 대장암의발생원인에있어유전적요인에의한암발생이 20% 만을차지하기에, 3 환경적요인을포함하여음식물에포함된 mutagen, 병원균, 만성장염증, 정상세균총 (microflora) 과종양유전자의상호작용등이관여할것으로생각하고있다. 4,5 암발생및진행에있어염증이어떠한역할을하는지에대한많은연구가있어왔는데 (Table 1), 6 대장암의경우대장염연관대장암 (colitis-associated cancer, CAC) 연구를통해만성염증이돌연변이, 혈관신생촉진, 세포자멸사 (apoptosis) 억제, 세포증식자극에관여함이밝혀졌고 7 이러한염증과정에관여하는많은유전자들을조절하는핵심전사인자인 nuclear factor kappa B (NF-κB) 의중요성이대두되고있다. 8 또한치료측면에서볼때많은항암제들이세포자멸사를유도하여종양세포의사멸을유도하기때문에세포자멸사를방해하는 NF-κB가항암예방의표적이되고있다. 9,10 이번원고에서는대장암발생에있어선천면역, 적응면역및염증의조절인자인 NF-κB가대장암발생기전에어떠한역할을수행하는지그리고치료에있어표적분자가될수있는지에대해알아보고자한다. CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 서검석, , 전북익산시신용동 344-2, 원광대학병원내과 Correspondence to: Geom Seog Seo, Department of Internal Medicine, Digestive Disease Research Institute, Wonkwang University College of Medicine, 344-2, Shinyong-dong, Iksan , Korea. Tel: , Fax: , medsgs@wonkwang.ac.kr Financial support: None. Conflicts of interest: None. Korean J Gastroenterol, Vol. 57 No. 1, January

2 4 서검석. 대장암에서 NF-κB 의역할 본론 1. NF-κB 신호전달경로 NF-κB는 5개의유전자로구성되어 NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), c-rel, RelB로구분할수있고, 자극이없는상태에서대부분의 NF-κB는억제단백 (inhibitory κb, IκB) 에의해세포질에존재한다. 포유동물에서는 2종류의 NF-κB 활성화경로가존재하는데하나는 classical (canonical) 경로이고다른하나는 non-classical (non-canonical) 경로이다. 자극인자로는 classical 경로의경우 lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), IL-1 α/β이고 non-classical 경로의경우 B-cell activating factor, which belong to the TNF family (BAFF), CD40 리간드, lymphotoxin β (LTβ) 이다. 이러한자극에의해 NF-κB의활성화가이루어지고, 이를조절하는것이 IKK (IκB kinase) 이다. 11 NF-κB의상위 kinase인 IKK 복합체는 α, β, γ 3개의성분으로구성되어있고, 이중 2개의 촉매아단위 (catalytic subunit) 는 α, β이고, 비촉매아단위 (noncatalytic subunit) 로는 IKKγ (NEMO) 가있다. IKKβ는 classical 경로활성화에, IKKα는 non-classical 경로의활성화에관여하고 IKKγ는조절역할을한다. Classical 경로는자극에의해 IKKβ가활성화되면인산화된 IκB는유비퀴틴화 (ubiquitination, 대표적인단백질의분해기전 ) 에의해분해되어, p50/p65 이합체가세포질에서핵으로이동한후, 핵안에서전사인자로작용하여면역조절, 세포증식, 세포생존및염증발생에관여한다. Non-classical 경로는자극에의해 IKKα가활성화되어 p100을인산화, 분해시켜 p52로변환시키고, 그결과로서만들어진 p52/relb 이합체가핵안으로이동하여 B 세포성숙, 이차림프기관발생에관여한다 (Fig. 1). 2. NF-κB에의한대장암발생기전 1) 대장염연관대장암궤양성대장염및크론병에서발생하는대장염연관대장 Table 1. Functional Relationship between Inflammation and Cancer 1. Tumors arise at sites of chronic inflammation 2. Inflammatory cells, chemokines and cytokines are present in tumors 3. Overexpression of cytokines and chemokines can induce cancer 4. The same molecular targets and similar pathways are activated or shut down in inflammation, as well as in the carcinogenesis process 5. Epidemiological studies have shown that chronic inflammatory states increase the risk of numerous cancers 6. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce the incidence and the mortality of several cancers Fig. 1. NF-κB signaling pathways. The Korean Journal of Gastroenterology

3 Seo GS. The Role of NF-κB in Colon Cancer 5 Table 2. Possible Roles of NF-κB in Colitis-associated Cancer 1. Dysregulated cytokine production and related signaling activation in inflamed gut 19 NF-κB activity correlated with the severity of inflammation 20 NF-κB activity TNF-α, IL-1 and IL-6 in macrophage ASA reduce NF-κB-mediated signaling reduce the risk of developing cancer 22,23 3. Experimental model 1) Conditional inactivation of the IKKβ gene within enterocytes 24 CAC incidence 2) The NBD peptide ameliorated colonic inflammatory injury through the downregulation of pro-inflammatory cytokines mediated by NF-κB inhibition in both models 25 암이전체인구에서발생하는대장암의 1-2% 만을차지하지만, 염증성장질환을가진환자에서사망원인의 15% 를차지한다. 최근보고에의하면염증성장질환을진단받고 8-10 년이경과한다음해마다 0.5-1% 씩대장암의위험도가증가함을보고하고있으며어린나이에진단, 긴증상발현기간, 전대장염의경우위험도가증가한다. 18 대장염연관대장암에서 NF-κB의역할을생각해보면, 첫째, 장상피세포및골수세포에서사이토카인생성조절장애및시그널활성화조절, 둘째, 치료적관점에서 NF-κB 관련신호전달이 5-ASA의표적이된다는점, 셋째, 동물실험에서 NF-κB 조절경로를불활성화또는억제하면암발생이감소한다는점이다 (Table 2). 2) 산발성대장암 (sporadic colon cancer) 대부분의산발성대장암은염증과관련없이발생가능하며 p53 유전자의불활성화가먼저발생하는대장염연관대장암과는달리 APC 불활성화가먼저발생하는것으로이해되고있다. 그러나최근연구에의해활성화된 NF-κB가이들산발성대장암의성장과진행에관여함이밝혀지고있다. 26,27 이렇게설명되는이유는 NF-κB가대장암환자의 40-80% 에서항상발현 (constitutive activation) 하고, 10,28 실험적으로 IKKγ를 sirna방법으로유전자발현을억제 (KD 세포 ) 하였을때 NFκB의항상발현이억제되었으며, IL-8, 성장조절알파단백 (Groα), monocyte chemoattractant protein-1 (MCP-1) 감소에따른혈관신생효과도차단되기때문이다 NF-κB가암발생및진행에미치는영향암발생및진행에있어성장시그널, 항세포사멸사, 혈관신생, 전이등이중요요소로알려져있다. 이러한과정에 NF-κB가어떻게관여하는지를이해하는것은치료에도움이되는표적물질을찾는데도움을줄수있다 (Table 3). 4. NF-κB가대장암치료를위한표적분자가될수있는가? Bortezomib (proteosome 억제제 ), IL-1β에의한 NF-κB 활성화및 IL-8 생성을모두억제하는 thalidomide, NF-κB 억제제인 arsenic trioxide 및덱사메타손등이대장암에효과 Table 3. How NF-κB Affects Cancer Development 1. Activator of antiapoptotic gene expression 29 C-FLIP, BCL-XL, A20 2. Effects on cell survival and production of growth NF-κB bind to Cyclin D1, D2 and D3 Control growth factor (HGF, G-CSF, BMP) 3. Regulator of angiogenesis 28,33 VEGF, Gro-α, IL-8, MCP-1 4. Promote metastasis of cancer cells Gelatinase (MMP-2, 9), EMT, Snail HGF, hepatocyte growth factor; BMP, bone morphogenetic protein; VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase; EMT, epithelial-to-mesenchymal transition. 가있다고일부보고되고있지만문제는 NF-κB가우리온몸에서다양한생리적활성을담당하기에 NF-κB 억제에의한변비, 말초신경염, 피부발적, 서맥, 혈전경향과같은독성부작용이발생할수있다는것이다 아직효과적인 NF-κB 관련억제제개발이되고있지않지만, 분자생물학적연구와약물전달법의발전에의해향후 NF-κB를표적으로하는 IL-1 수용체길항제, IKKs 및 IκBs 억제제, NEMO binding domain peptide (NBD), Inhibitor of apoptosis (IAP) 등이표적분자가될것으로기대되고있다. 42 결 론 NF-κB는염증과정에관여하는많은유전자들을조절하는핵심전사인자로서대장암을비롯한여러암의발생및진행에관여함이밝혀지고있어이에대한이해가중요하다할수있으며많은연구를통해천연물, 합성물, 투과성펩타이드등이 NF-κB 활성을억제한다고밝혀져있다. 이처럼 NF-κB 를이용한약제개발에노력하는이유는 NF-κB가성장신호전달, 항세포사멸사, 혈관신생, 전이등의전과정에관여하고, 실제대장암환자의조직에서항시발현이높아, NF-κB와조절인자인 IKK, IκB 등이항암치료에있어표적분자가될 Vol. 57 No. 1, January 2011

4 6 서검석. 대장암에서 NF-κB 의역할 수있을것으로기대되기때문이다. 그러나, NF-κB는염증, 암발생과정뿐만아니라다른여러생리적활성에도관여하기때문에치료제로활용되기위해서는부작용을최소화시키면서광범위한면역억제를피할수있는 NF-κB 표적물질의개발이필요한데, 이렇게된다면대장암치료에있어새로운희망이될수있을것이다. 감사의글 본논문의내용에대해과학적견해를제시해주신약대이성희박사님께감사드립니다. REFERENCES 1. Koh SJ, Kim JS. The reasons for the increased incidence of colorectal cancer in Korea. Korean J Med 2010;79: Tenesa A, Dunlop MG. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet 2009;10: Rustgi AK. The genetics of hereditary colon cancer. Genes Dev 2007;21: Terzić J, Grivennikov S, Karin E, Karin M. Inflammation and colon cancer. Gastroenterology 2010;138: Lee SH, Hu LL, Gonzalez-Navajas J, et al. ERK activation drives intestinal tumorigenesis in Apc (min/+) mice. Nat Med 2010;16: Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454: Kundu JK, Surh YJ. Inflammation: gearing the journey to cancer. Mutat Res 2008;659: Baud V, Karin M. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 2009;8: Burstein E, Fearon ER. Colitis and cancer: a tale of inflammatory cells and their cytokines. J Clin Invest 2008;118: Lind DS, Hochwald SN, Malaty J, et al. Nuclear factor-κb is upregulated in colorectal cancer. Surgery 2001;130: DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-κB. Nature 1997;388: Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48: Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990;323: Gyde SN, Prior P, Macartney JC, Thompson H, Waterhouse JA, Allan RN. Malignancy in Crohn s disease. Gut 1980;21: Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001;91: 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: Freeman HJ. Colorectal cancer risk in Crohn s disease. World J Gastroenterol 2008;14: Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001;91: Atreya I, Atreya R, Neurath MF. NF-κB in inflammatory bowel disease. J Intern Med 2008;263: Rogler G, Brand K, Vogl D, et al. Nuclear factor κb is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 1998;115: Neurath MF, Fuss I, Schürmann G, et al. Cytokine gene transcription by NF-κB family members in patients with inflammatory bowel disease. Ann NY Acad Sci 1998; 859: Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther 2003;18(Suppl 2): Yan F, Polk DB. Aminosalicylic acid inhibits IkB kinase alpha phosphorylation of IκB alpha in mouse intestinal epithelial cells. J Biol Chem 1999;274: Greten FR, Eckmann L, Greten TF, et al. IKK beta links inflammation and tumorigenesis in amouse model of colitis-associated cancer. Cell 2004;118: Shibata W, Maeda S, Hikiba Y, et al. Cutting edge: the IκB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks inflammatory injury in murine colitis. J Immunol 2007;179: Karin M, Cao Y, Greten FR, Li ZW. NF-κB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002;2: Horst D, Budczies J, Brabletz T, Kirchner T, Hlubek F. Invasion associated up-regulation of nuclear factor kappab target genes in colorectal cancer. Cancer 2009; 115: Sakamoto K, Maeda S, Hikiba Y, et al. Constitutive NF-κ B activation in colorectal carcinoma plays a key role in angiogenesis, promoting tumor growth. Clin Cancer Res 2009;15: Luo JL, Kamata H, Karin M. IKK/NF-κB signaling: balancing life and death--a new approach to cancer therapy. J The Korean Journal of Gastroenterology

5 Seo GS. The Role of NF-κB in Colon Cancer 7 Clin Invest 2005;115: Joyce D, Albanese C, Steer J, Fu M, Bouzahzah B, Pestell RG. NF-κB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev 2001;12: Hanada T, Yoshimura A. Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev 2002; 13: 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):iii Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link? Biochem Pharmacol 2006;72: Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2: Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 2009;28: Huber MA, Azoitei N, Baumann B, et al. NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004;114: Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP. Stabilization of snail by NF-κB is required for inflammation-induced cell migration and invasion. Cancer Cell 2009;15: 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: Singhal S, Mehta J. Thalidomide in cancer: potential uses and limitations. BioDrugs 2001;15: Subbarayan PR, Lima M, Ardalan B. Arsenic trioxide/ascorbic acid therapy in patients with refractory metastatic colorectal carcinoma: a clinical experience. Acta Oncol 2007;46: Kemeny N, Capanu M, D Angelica M, et al. Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer. Ann Oncol 2009;20: Sakamoto K, Maeda S. Targeting NF-kappaB for colorectal cancer. Expert Opin Ther Targets 2010;14: Vol. 57 No. 1, January 2011

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract