Targeting IL-17A: A New Frontier in the Treatment of Colitis-Associated Cancer

Authors

  • Ashok Kumar Pandurangan School of Life Sciences, B.S. Abdur Rahman Crescent Institute of Science and Technology, Vandalur, Chennai, India Author

DOI:

https://doi.org/10.64229/2ew2fm31

Keywords:

Colitis associated cancer, Cytokines, IL-17A, Cocoa, Embelin

Abstract

Ulcerative colitis (UC) is characterized by chronic inflammation in the colon that can lead to the development of colitis-associated cancer if left untreated. Interleukin-17A (IL-17A), an inflammatory cytokine produced by Th17 cells, plays a crucial role in mediating inflammatory reactions in autoimmune diseases like inflammatory bowel disease and has been implicated in colitis associated cancer development. This review discusses the importance of IL-17A in colitis associated cancer pathogenesis and examines novel therapies targeting IL-17A as potential treatments. Evidence from animal studies demonstrates that inhibition of IL-17A signaling can suppress intestinal inflammation and tumor development in colitis associated cancer models. Several natural compounds like cocoa, embelin, β-carotene, and melatonin have shown promise in reducing IL-17A expression and colitis associated cancer progression in preclinical studies. Additionally, administration of IL-17A antibodies has been found to decrease tumor formation in mouse models of colitis associated cancer. Recent research has also revealed the role of microRNAs like microRNA-146a in modulating IL-17 responses and limiting tumorigenic inflammation. While further research is needed, targeting the IL-17A pathway represents a promising therapeutic approach for preventing and treating colitis associated cancer. This review summarizes the current evidence supporting IL-17A as a key mediator of colitis associated cancer and highlights potential strategies to inhibit this pathway for therapeutic benefit.

References

[1]Shah SC, Itzkowitz SH. Colorectal cancer in inflammatory bowel disease: mechanisms and management. Gastroenterology, 2022, 162(3), 715-730. e3. DOI: 10.1053/j.gastro.2021.10.035

[2]Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature, 2008, 454(7203), 436-444. DOI: 10.1038/nature07205

[3]Gupta RB, Harpaz N, Itzkowitz S, Hossain S, Matula S, Kornbluth A, et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology, 2007, 133(4), 1099-1105; quiz 1340-1. DOI: 10.1053/j.gastro.2007.08.001

[4]Rutter M, Saunders B, Wilkinson K, Rumbles S, Schofield G, Kamm M, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology, 2004, 126(2), 451-459. DOI: 10.1053/j.gastro.2003.11.010

[5]Pandurangan AK, Saadatdoust Z, Esa NM, Hamzah H, Ismail A. Dietary cocoa protects against colitis-associated cancer by activating the Nrf2/Keap1 pathway. Biofactors, 2015, 41(1), 1-14. DOI: 10.1002/biof.1195

[6]Stolfi C, Rizzo A, Franzè E, Rotondi A, Fantini MC, Sarra M, et al. Involvement of interleukin-21 in the regulation of colitis-associated colon cancer. The Journal of experimental medicine, 2011, 208(11), 2279-2290. DOI: 10.1084/jem.20111106

[7]Pandurangan AK, Esa NM. Signal transducer and activator of transcription 3-a promising target in colitis-associated cancer. Asian Pacific journal of cancer prevention, 2014;15(2):551-560. DOI: 10.7314/apjcp.2014.15.2.551

[8]Pandurangan AK, Ismail S, Saadatdoust Z, Esa NM. Allicin Alleviates dextran sodium sulfate-(DSS-) induced ulcerative colitis in BALB/c mice. Oxidative Medicine and Cellular Longevity, 2015, 2015, 605208. DOI: 10.1155/2015/605208

[9]Pandurangan AK, Mohebali N, Mohd Esa N, Looi CY, Ismail S, Saadatdoust Z. Gallic acid suppresses inflammation in dextran sodium sulfate-induced colitis in mice: Possible mechanisms. International immunopharmacology, 2015, 28(2), 1034-1043. DOI: 10.1016/j.intimp.2015.08.019

[10]Hisamatsu T, Miyoshi J, Oguri N, Morikubo H, Saito D, Hayashi A, et al. Inflammation-associated carcinogenesis in inflammatory bowel disease: Clinical features and molecular mechanisms. Cells, 2025, 14(8), 567. DOI: 10.3390/cells14080567

[11]Koyyala VPB, Kantharia C, Darooka N, Kumar M, Ranjan P, Anikhindi S, et al. Inflammatory bowel disease and colorectal cancer: An eternal fire in a beautiful garden. South Asian Journal of Cancer, 2025, 13(4), 300-304. DOI: 10.1055/s-0045-1802335

[12]Liu M, Yang C, Peng X, Zheng S, He H, Wang W, et al. Formononetin suppresses colitis-associated colon cancer by targeting lipid synthesis and mTORC2/Akt signaling. Phytomedicine, 2025, 142, 156665. DOI: 10.1016/j.phymed.2025.156665

[13]Yamamoto-Furusho JK, Gutierrez-Herrera FD. Molecular mechanisms and clinical aspects of colitis-associated cancer in ulcerative colitis. Cells, 2025, 14(3), 162. DOI: 10.3390/cells14030162

[14]Neuman MG. Immune dysfunction in inflammatory bowel disease. Translational Research: The Journal of Laboratory and Clinical Medicine, 2007, 149(4), 173-186. DOI: 10.1016/j.trsl.2006.11.009

[15]Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Reviews, 2003, 14(2), 155-174. DOI: 10.1016/s1359-6101(03)00002-9

[16]Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, Hewett DR, et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. Journal of Experimental Medicine, 2006, 203(4), 1105-1116. DOI: 10.1084/jem.20051615

[17]Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity, 2001, 15(6), 985-995. DOI: 10.1016/s1074-7613(01)00243-6

[18]Owyang AM, Zaph C, Wilson EH, Guild KJ, McClanahan T, Miller HR, et al. Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. Journal of Experimental Medicine, 2006, 203(4), 843-849. DOI: 10.1084/jem.20051496

[19]Abraham C, Cho J. Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflammatory Bowel Diseases. 2009, 15(7), 1090-1100. DOI: 10.1002/ibd.20894

[20]Koenders MI, van den Berg WB. Translational mini-review series on Th17 cells: are T helper 17 cells really pathogenic in autoimmunity? Clinical and Experimental Immunology, 2010, 159(2), 131-136. DOI: 10.1111/j.1365-2249.2009.04039.x

[21]Brown J, Martin M, Wang H, Hajishengallis GN. TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. Journal of Dental Research, 2010, 90(4), 417-427. DOI: 10.1177/0022034510381264

[22]Che KF, Sun J, Lindén A, Lappi-Blanco E, Levänen B, Sköld CM, et al. Interleukin-26 production in human primary bronchial epithelial cells in response to viral stimulation: Modulation by Th17 cytokines. Molecular Medicine, 2017, 23(1), 247-257. DOI: 10.2119/molmed.2016.00064

[23]Jiang R, Sun B. IL-22 Signaling in the tumor microenvironment. Advances in Experimental Medicine and Biology, 2021, 1290, 81-88. DOI: 10.1007/978-3-030-55617-4_5

[24]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. DOI: 10.1136/gut.2008.163667

[25]Ito R, Kita M, Shin-Ya M, Kishida T, Urano A, Takada R, et al. Involvement of IL-17A in the pathogenesis of DSS-induced colitis in mice. Biochemical and Biophysical Research Communications, 2008, 377(1), 12-16. DOI: 10.1016/j.bbrc.2008.09.019

[26]Chae WJ, Gibson TF, Zelterman D, Hao L, Henegariu O, Bothwell AL. Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(12), 55405544. DOI: 10.1073/pnas.0912675107

[27]Tâlvan ET, Budișan L, Mohor CI, Grecu V, Berindan-Neagoe I, Cristea V, et al. Interleukin dynamics and their correlation with tumor aggressiveness in colorectal carcinoma. International Journal of Molecular Sciences, 2025, 26(14):7027. DOI: 10.3390/ijms26147027.

[28]Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature medicine, 2009, 15(9), 1016-1022. DOI: 10.1038/nm.2015.

[29]Xie Z, Qu Y, Leng Y, Sun W, Ma S, Wei J, et al. Human colon carcinogenesis is associated with increased interleukin-17-driven inflammatory responses. Drug Design, Development and Therapy, 2015, 9, 1679-1689. DOI: 10.2147/DDDT.S79431

[30] Hyun YS, Han DS, Lee AR, Eun CS, Youn J, Kim HY. Role of IL-17A in the development of colitis-associated cancer. Carcinogenesis, 2012, 33(4), 931-936. DOI: 10.1093/carcin/bgs106

[31]Qi H, Yang H, Xu G, Ren J, Hua W, Shi Y, et al. Therapeutic efficacy of IL-17A antibody injection in preventing the development of colitis associated carcinogenesis in mice. Immunobiology, 2015, 220(1), 54-59. DOI: 10.1016/j.imbio.2014.09.002

[32]Fantini MC, Pallone F. Cytokines: from gut inflammation to colorectal cancer. Curr Drug Targets, 2008, 9(5), 375-380. DOI: 10.2174/138945008784221206

[33]Girondel C, Lévesque K, Langlois MJ, Pasquin S, Saba-El-Leil MK, Rivard N, et al. Loss of interleukin-17 receptor D promotes chronic inflammation-associated tumorigenesis. Oncogene, 2021, 40(2), 452-464. DOI: 10.1038/s41388-020-01540-4

[34]Garo LP, Ajay AK, Fujiwara M, Gabriely G, Raheja R, Kuhn C, et al. MicroRNA-146a limits tumorigenic inflammation in colorectal cancer. Nature Communications, 2021, 12(1), 2419. DOI: 10.1038/s41467-021-22641-y

[35]Saadatdoust Z, Pandurangan AK, Ananda Sadagopan SK, Mohd Esa N, Ismail A, Mustafa MR. Dietary cocoa inhibits colitis associated cancer: a crucial involvement of the IL-6/STAT3 pathway. Journal of Nutritional Biochemistry, 2015, 26(12), 1547-1558. DOI: 10.1016/j.jnutbio.2015.07.024

[36]Dai Y, Jiao H, Teng G, Wang W, Zhang R, Wang Y, et al. Embelin reduces colitis-associated tumorigenesis through limiting IL-6/STAT3 signaling. Molecular Cancer Therapeutics, 2014, 13(5), 1206-1216. DOI: 10.1158/1535-7163.MCT-13-0378

[37]Trivedi PP, Jena GB. Mechanistic insight into beta-carotene-mediated protection against ulcerative colitis-associated local and systemic damage in mice. European Journal of Nutrition, 2015, 54(4), 639-652. DOI: 10.1007/s00394-014-0745-5

[38]rivedi PP, Jena GB, Tikoo KB, Kumar V. Melatonin modulated autophagy and Nrf2 signaling pathways in mice with colitis-associated colon carcinogenesis. Molecular Carcinogenesis, 2016, 55(3), 255-267. DOI: 10.1002/mc.22274

[39]Pan D, Huang B, Gan Y, Gao C, Liu Y, Tang Z. Phycocyanin Ameliorates Colitis-Associated Colorectal Cancer by Regulating the Gut Microbiota and the IL-17 Signaling Pathway. Marine Drugs, 2022, 20(4), 260. DOI: 10.3390/md20040260.

[40]Luo Q, Huang S, Zhao L, Liu J, Ma Q, Wang Y, et al. Chang qing formula ameliorates colitis-associated colorectal cancer via suppressing IL-17/NF-κB/STAT3 pathway in mice as revealed by network pharmacology study. Frontiers in Pharmacology, 2022, 13, 893231. DOI: 10.3389/fphar.2022.893231

[41]Yun X, Zhang Q, Fang Y, Lv C, Chen Q, Chu Y, et al. Madecassic acid alleviates colitis-associated colorectal cancer by blocking the recruitment of myeloid-derived suppressor cells via the inhibition of IL-17 expression in γδT17 cells. Biochemical Pharmacology, 2022, 202, 115138. DOI: 10.1016/j.bcp.2022.115138

[42]Duan Y, Lu Y, Liu Z, Zhang J, Yang Z, Guo Y, et al. Qingre Huayu Jianpi prescription alleviates the inflammatory transformation of colitis-associated colorectal cancer by inhibiting the IL-17RA/ACT1/NF-κB axis. Journal of Ethnopharmacology, 2025, 345, 119554. DOI: 10.1016/j.jep.2025.119554

[43]Liang J, Dai W, Liu C, Wen Y, Chen C, Xu Y, et al. Gingerenone A attenuates ulcerative colitis via targeting IL-17RA to inhibit inflammation and restore intestinal barrier function. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2024, 11(28), e2400206. DOI: 10.1002/advs.202400206

[44]Wang L, Zhang QQ, Xu YY, Zhang R, Zhao Q, Zhang YQ, et al. Ginsenoside Rb1 suppresses AOM/DSS-induced colon carcinogenesis. Anti-cancer Agents in Medicinal Chemistry, 2023, 23(9), 1067-1073. DOI: 10.2174/1871520623666230119092735

[45]Yang X, Wang Q, Zhang X, Li L, Cao X, Zhou L, et al. Purple yam polyphenol extracts exert anticolitis and anticolitis-associated colorectal cancer effects through inactivation of NF-κB/p65 and STAT3 signaling pathways.Journal of Agricultural and Food Chemistry, 2023, 71(32), 12177-12189. DOI: 10.1021/acs.jafc.3c00346

[46]Dong M, Liu H, Cao T, Li L, Sun Z, Qiu Y, et al. Huoxiang Zhengqi alleviates azoxymethane/dextran sulfate sodium-induced colitis-associated cancer by regulating Nrf2/NF-κB/NLRP3 signaling. Frontiers in Pharmacology, 2022, 13, 1002269. DOI: 10.3389/fphar.2022.1002269

[47]Veronez LC, Silveira DSCD, Lopes-Júnior LC, Dos Santos JC, Barbisan LF, Pereira-da-Silva G. Jacalin attenuates colitis-associated colorectal carcinogenesis by inhibiting tumor cell proliferation and intestinal inflammation. Inflammatory Bowel Diseases, 2025, 31(5), 1344-1354. DOI: 10.1093/ibd/izae303

[48]Hwang S, Jo M, Hong JE, Kim WS, Kang DH, Yoo SH, et al. Caffeic acid phenethyl ester administration reduces enterotoxigenic bacteroides fragilis-induced colitis and tumorigenesis. Toxins, 2024, 16(9), 403. DOI: 10.3390/toxins16090403

[49]Pinos I, Coronel J, Albakri A, Blanco A, McQueen P, Molina D, et al. β-Carotene accelerates the resolution of atherosclerosis in mice. Elife, 2024, 12, RP87430. DOI: 10.7554/eLife.87430

[50]von Lintig J. Eat your carrots! β-Carotene and cholesterol homeostasis. The Journal of Nutrition, 2020, 150(8), 2003-2005. DOI: 10.1093/jn/nxaa189

[51]Shih YH, Chen CC, Kuo YH, Fuh LJ, Lan WC, Wang TH, et al. Caffeic acid phenethyl ester and caffeamide derivatives suppress oral squamous cell carcinoma cells. International Journal of Molecular Sciences, 2023, 24(12), 9819. DOI: 10.3390/ijms24129819

[52]Pandurangan AK, Mohebali N, Hasanpourghadi M, Esa NM. Caffeic acid phenethyl ester attenuates dextran sulfate sodium-induced ulcerative colitis through modulation of NF-κB and cell adhesion molecules. Applied Biochemistry and Biotechnology, 2022, 194(3), 1091-1104. DOI: 10.1007/s12010-021-03788-2

Downloads

Published

2025-10-24

Issue

Section

Articles