Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

IL-22 is related to development of human colon cancer by activation of STAT3

Authors: Runqiu Jiang, Haiyang Wang, Lei Deng, Jiajie Hou, Ruihua Shi, Ming Yao, Yun Gao, Aihua Yao, Xuehao Wang, Lianzhen Yu, Beicheng Sun

Published in: BMC Cancer | Issue 1/2013

Login to get access

Abstract

Background

It has been previously reported that IL-22, one of the cytokines secreted by Th17 cells, demonstrates both a protective and inflammatory promotion effect in inflammatory bowel disease (IBD) through STAT3 signaling activation. We sought to investigate the role of IL-22 expression in colon cancer (CC).

Methods

The expression of IL-22 and related molecules were detected in human CC, the detail function and mechanism of IL-22 were investigated by in vivo and in vitro model.

Results

Our results demonstrated significant upregulation of IL-22 in human CC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, our findings demonstrated that IL-22 expression was significantly higher in ulcerative colitis (UC) tissues versus normal colon tissues. Both IL-22 receptor α1 (IL-22RA1) and IL-23 were highly expressed in CC and UC tissues compared to normal controls. TILs exhibiting various IL-22 expression levels isolated from CC patients were demonstrated to enhance tumor growth and metastasis co-transplanted with Hct-116 cells underwent subcutaneous transplantation in mice model. Tumor growth and metastasis was promoted by STAT3 phosphorylation and upregulation of its downstream genes such as Bcl-xl, CyclinD1, and VEGF. In vitro studies confirmed the anti-apoptotic and pro-proliferation effect of IL-22 according to the BrdU cooperation assay and peroxide induced apoptosis analysis with or without the presence of IL-22.

Conclusion

In this study we demonstrated that excessive IL-22 in the CC and UC microenvironment leads to tumor growth, inhibition of apoptosis, and promotion of metastasis depend on STAT3 activation.
Appendix
Available only for authorised users
Literature
1.
Denlinger CS, Engstrom PF: Colorectal cancer survivorship: movement matters. Cancer Prev Res (Phila). 2011, 4 (4): 502-511. 10.1158/1940-6207.CAPR-11-0098.CrossRef
2.
3.
Ekbom A, Helmick C, Zack M, Adami HO: Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. 1990, 323 (18): 1228-1233. 10.1056/NEJM199011013231802.CrossRefPubMed
4.
Medema JP, Vermeulen L: Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature. 2011, 474 (7351): 318-326. 10.1038/nature10212.CrossRefPubMed
5.
Terzic J, Grivennikov S, Karin E, Karin M: Inflammation and colon cancer. Gastroenterology. 2010, 138 (6): 2101-2114. 10.1053/j.gastro.2010.01.058. e2105CrossRefPubMed
6.
Levy DE, Darnell JE: Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002, 3 (9): 651-662.CrossRefPubMed
7.
Yu H, Kortylewski M, Pardoll D: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007, 7 (1): 41-51. 10.1038/nri1995.CrossRefPubMed
8.
He G, Karin M: NF-kappaB and STAT3 - key players in liver inflammation and cancer. Cell Res. 2011, 21 (1): 159-168. 10.1038/cr.2010.183.CrossRefPubMed
9.
Lees CW, Barrett JC, Parkes M, Satsangi J: New IBD genetics: common pathways with other diseases. Gut. 2011, 60 (12): 1739-1753. 10.1136/gut.2009.199679.CrossRefPubMed
10.
Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T, Nebelsiek T, Lundgren-May T, Canli O, Schwitalla S: gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 2009, 15 (2): 91-102. 10.1016/j.ccr.2009.01.002.CrossRefPubMed
11.
Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L: IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009, 15 (2): 103-113. 10.1016/j.ccr.2009.01.001.CrossRefPubMedPubMedCentral
12.
Lin L, Liu A, Peng Z, Lin HJ, Li PK, Li C, Lin J: STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res. 2011, 71 (23): 7226-7237. 10.1158/0008-5472.CAN-10-4660.CrossRefPubMedPubMedCentral
13.
Matsumoto S, Hara T, Mitsuyama K, Yamamoto M, Tsuruta O, Sata M, Scheller J, Rose-John S, Kado S, Takada T: Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model. J Immunol. 2010, 184 (3): 1543-1551. 10.4049/jimmunol.0801217.CrossRefPubMed
14.
Steinbrecher KA, Horowitz NA, Blevins EA, Barney KA, Shaw MA, Harmel-Laws E, Finkelman FD, Flick MJ, Pinkerton MD, Talmage KE: Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen. Cancer Res. 2010, 70 (7): 2634-2643. 10.1158/0008-5472.CAN-09-3465.CrossRefPubMedPubMedCentral
15.
Strober W, Fuss IJ: Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011, 140 (6): 1756-1767. 10.1053/j.gastro.2011.02.016.CrossRefPubMedPubMedCentral
16.
Dong C: TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008, 8 (5): 337-348. 10.1038/nri2295.CrossRefPubMed
17.
Reiner SL: Development in motion: helper T cells at work. Cell. 2007, 129 (1): 33-36. 10.1016/j.cell.2007.03.019.CrossRefPubMed
18.
Abraham C, Medzhitov R: Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology. 2011, 140 (6): 1729-1737. 10.1053/j.gastro.2011.02.012.CrossRefPubMedPubMedCentral
19.
Morrison PJ, Ballantyne SJ, Kullberg MC: Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity. Immunology. 2011, 133 (4): 397-408. 10.1111/j.1365-2567.2011.03454.x.CrossRefPubMedPubMedCentral
20.
Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F: Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007, 8 (9): 942-949. 10.1038/ni1496.CrossRefPubMed
21.
Das J, Ren G, Zhang L, Roberts AI, Zhao X, Bothwell AL, Van Kaer L, Shi Y, Das G: Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med. 2009, 206 (11): 2407-2416. 10.1084/jem.20082286.CrossRefPubMedPubMedCentral
22.
Erreni M, Mantovani A, Allavena P: Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer. Cancer Microenviron. 2011, 4 (2): 141-154. 10.1007/s12307-010-0052-5.CrossRefPubMed
23.
Manel N, Unutmaz D, Littman DR: The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 2008, 9 (6): 641-649. 10.1038/ni.1610.CrossRefPubMedPubMedCentral
24.
Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, Lin Z, Zhu B: IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma. Biochem Biophys Res Commun. 2011, 407 (2): 348-354. 10.1016/j.bbrc.2011.03.021.CrossRefPubMed
25.
Radosavljevic G, Ljujic B, Jovanovic I, Srzentic Z, Pavlovic S, Zdravkovic N, Milovanovic M, Bankovic D, Knezevic M, Acimovic LJ: Interleukin-17 may be a valuable serum tumor marker in patients with colorectal carcinoma. Neoplasma. 2010, 57 (2): 135-144. 10.4149/neo_2010_02_135.CrossRefPubMed
26.
Yang S, Wang B, Guan C, Wu B, Cai C, Wang M, Zhang B, Liu T, Yang P: Foxp3 + IL-17+ T cells promote development of cancer-initiating cells in colorectal cancer. J Leukoc Biol. 2011, 89 (1): 85-91. 10.1189/jlb.0910506.CrossRefPubMed
27.
Kryczek I, Wei S, Szeliga W, Vatan L, Zou W: Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood. 2009, 114 (2): 357-359. 10.1182/blood-2008-09-177360.CrossRefPubMedPubMedCentral
28.
Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R: IL-22 increases the innate immunity of tissues. Immunity. 2004, 21 (2): 241-254. 10.1016/j.immuni.2004.07.007.CrossRefPubMed
29.
Thompson CL, Plummer SJ, Tucker TC, Casey G, Li L: Interleukin-22 genetic polymorphisms and risk of colon cancer. Cancer Causes Control. 2010, 21 (8): 1165-1170. 10.1007/s10552-010-9542-5.CrossRefPubMed
30.
Nagakawa H, Shimozato O, Yu L, Takiguchi Y, Tatsumi K, Kuriyama T, Tagawa M: Expression of interleukin-22 in murine carcinoma cells did not influence tumour growth in vivo but did improve survival of the inoculated hosts. Scand J Immunol. 2004, 60 (5): 449-454. 10.1111/j.0300-9475.2004.01504.x.CrossRefPubMed
31.
Fukui H, Sekikawa A, Tanaka H, Fujimori Y, Katake Y, Fujii S, Ichikawa K, Tomita S, Imura J, Chiba T: DMBT1 is a novel gene induced by IL-22 in ulcerative colitis. Inflamm Bowel Dis. 2011, 17 (5): 1177-1188. 10.1002/ibd.21473.CrossRefPubMed
32.
Sekikawa A, Fukui H, Suzuki K, Karibe T, Fujii S, Ichikawa K, Tomita S, Imura J, Shiratori K, Chiba T: Involvement of the IL-22/REG Ialpha axis in ulcerative colitis. Lab Invest. 2010, 90 (3): 496-505. 10.1038/labinvest.2009.147.CrossRefPubMed
33.
Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, Cianfarani F, Odorisio T, Traidl-Hoffmann C, Behrendt H: Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest. 2009, 119 (12): 3573-3585.PubMedPubMedCentral
34.
Jiang R, Tan Z, Deng L, Chen Y, Xia Y, Gao Y, Wang X, Sun B: Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology. 2011, 54 (3): 900-909. 10.1002/hep.24486.CrossRefPubMed
35.
Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, Tsujikawa T, Kitoh K, Kim-Mitsuyama S, Takayanagi A: Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology. 2005, 129 (3): 969-984. 10.1053/j.gastro.2005.06.071.CrossRefPubMed
36.
Wolk K, Witte E, Witte K, Warszawska K, Sabat R: Biology of interleukin-22. Semin Immunopathol. 2010, 32 (1): 17-31. 10.1007/s00281-009-0188-x.CrossRefPubMed
37.
Zhang N, Pan HF, Ye DQ: Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol Cell Biochem. 2011, 353 (1–2): 41-46.CrossRefPubMed
38.
Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, Mention JJ, Thiam K, Cerf-Bensussan N, Mandelboim O: Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity. 2008, 29 (6): 958-970. 10.1016/j.immuni.2008.11.001.CrossRefPubMed
39.
Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, Blumberg RS, Xavier RJ, Mizoguchi A: IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008, 118 (2): 534-544.PubMedPubMedCentral
40.
Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M, Lehr HA, Hirth S, Weigmann B, Wirtz S: STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med. 2009, 206 (7): 1465-1472. 10.1084/jem.20082683.CrossRefPubMedPubMedCentral
41.
Demetris AJ, Lunz JG, Specht S, Nozaki I: Biliary wound healing, ductular reactions, and IL-6/gp130 signaling in the development of liver disease. World J Gastroenterol. 2006, 12 (22): 3512-3522.CrossRefPubMedPubMedCentral
42.
Neufert C, Pickert G, Zheng Y, Wittkopf N, Warntjen M, Nikolaev A, Ouyang W, Neurath MF, Becker C: Activation of epithelial STAT3 regulates intestinal homeostasis. Cell Cycle. 2010, 9 (4): 652-655. 10.4161/cc.9.4.10615.CrossRefPubMed
43.
te Velde AA, de Kort F, Sterrenburg E, Pronk I, ten Kate FJ, Hommes DW, van Deventer SJ: Comparative analysis of colonic gene expression of three experimental colitis models mimicking inflammatory bowel disease. Inflamm Bowel Dis. 2007, 13 (3): 325-330. 10.1002/ibd.20079.CrossRefPubMed
44.
Huber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L, Hu B, Hedl M, Zhang W, O'Connor W, Murphy AJ: IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature. 2012, 491 (7423): 259-263. 10.1038/nature11535.CrossRefPubMedPubMedCentral
45.
Radaeva S, Sun R, Pan HN, Hong F, Gao B: Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology. 2004, 39 (5): 1332-1342. 10.1002/hep.20184.CrossRefPubMed
46.
Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA: Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity. 2007, 27 (4): 647-659. 10.1016/j.immuni.2007.07.023.CrossRefPubMedPubMedCentral
47.
Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S, Ki SH, Yoo SH, Dooley S, Wang FS: In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology. 2011, 54 (1): 252-261. 10.1002/hep.24339.CrossRefPubMedPubMedCentral
48.
Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, Pestka S: Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J Biol Chem. 2001, 276 (4): 2725-2732. 10.1074/jbc.M007837200.CrossRefPubMed
49.
Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, Wood WI, Goddard AD, Gurney AL: Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J Biol Chem. 2000, 275 (40): 31335-31339.CrossRefPubMed
50.
Jones BC, Logsdon NJ, Walter MR: Structure of IL-22 bound to its high-affinity IL-22R1 chain. Structure. 2008, 16 (9): 1333-1344. 10.1016/j.str.2008.06.005.CrossRefPubMedPubMedCentral
51.
Brand S: Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut. 2009, 58 (8): 1152-1167. 10.1136/gut.2008.163667.CrossRefPubMed
52.
Hruz P, Dann SM, Eckmann L: STAT3 and its activators in intestinal defense and mucosal homeostasis. Curr Opin Gastroenterol. 2010, 26 (2): 109-115. 10.1097/MOG.0b013e3283365279.CrossRefPubMed
Metadata
Title
IL-22 is related to development of human colon cancer by activation of STAT3
Authors
Runqiu Jiang
Haiyang Wang
Lei Deng
Jiajie Hou
Ruihua Shi
Ming Yao
Yun Gao
Aihua Yao
Xuehao Wang
Lianzhen Yu
Beicheng Sun
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-59

Other articles of this Issue 1/2013

BMC Cancer 1/2013 Go to the issue

Research article

Aluminum concentrations in central and peripheral areas of malignant breast lesions do not differ from those in normal breast tissues

Research article

The Glasgow Prognostic Score, an inflammation based prognostic score, predicts survival in patients with hepatocellular carcinoma

Research article

The relationship of Vascular endothelial growth factor gene polymorphisms and clinical outcome in advanced gastric cancer patients treated with FOLFOX: VEGF polymorphism in gastric cancer

Research article

FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801

Research article

HOXB7 mRNA is overexpressed in pancreatic ductal adenocarcinomas and its knockdown induces cell cycle arrest and apoptosis

Research article

Effects of hypoxia on human cancer cell line chemosensitivity
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits