Abstract
Interleukin-17 (IL-17) is a pro-inflammatory cytokine found in various cancers. Current evidence indicates that IL-17 plays a vital role in tumour initiation and progression in colorectal carcinoma (CRC) via binding with its receptor, IL-17RA. However, the association between clinicopathological features and presence of IL-17 and IL-17RA protein in primary CRC tissues remains unclear. This study also investigates the difference between the presence of IL-17 and IL-17RA in the paired tumour tissues versus adjacent normal tissues. The presence of IL-17RA and IL-17 protein in primary CRC tissues was determined by immunohistochemistry. Associations between clinicopathological features and IL-17RA and IL-17 immunoreactivity, were analyzed by χ2 tests. We found that both IL-17RA (p = 0.001) and IL-17 (p = 0.025) in tumour cells of primary CRC tissues was significantly lower as compared to adjacent normal tissue. Positive immunoreactivity for IL-17RA and IL-17 were detected in 51.0% and 16.8% of tumour tissues, respectively. Furthermore, negative immunoreactivity of IL-17R was significantly associated with advanced stage according to TNM classifier (p = 0.027), high grade of tumour (p = 0.019), increased depth of tumour invasion (p = 0.023) and vascular invasion (p = 0.039). Positive IL-17 immunoreactivity was associated with advanced stage (p = 0.008) and lymph node metastasis (p = 0.008). Thus, this study suggests that the loss of IL-17RA expression occurs as tumour progresses and this may predict the aggressiveness of tumour whilst expression of IL-17 promotes tumour progression and lymph node metastasis. Thus, loss of IL-17RA could be a useful prognostic biomarker for tumour progression in CRC patients.
Similar content being viewed by others
References
Erreni M, Mantovani A, Allavena P (2011) Tumor-associated Macrophages (TAM) and inflammation in colorectal cancer. Cancer Microenviron 4(2):141–154. https://doi.org/10.1007/s12307-010-0052-5
Pernot S, Terme M, Voron T, Colussi O, Marcheteau E, Tartour E, Taieb J (2014) Colorectal cancer and immunity: what we know and perspectives. World J Gastroenterol 20(14):3738–3750. https://doi.org/10.3748/wjg.v20.i14.3738
Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, Ostos LC, Lannon WA, Grotzinger C, Del Rio M, Lhermitte B, Olshen AB, Wiedenmann B, Cantley LC, Gray JW, Hanahan D (2013) A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 19(5):619–625. https://doi.org/10.1038/nm.3175
Misiakos EP, Karidis NP, Kouraklis G (2011) Current treatment for colorectal liver metastases. World J Gastroenterol 17(36):4067–4075. https://doi.org/10.3748/wjg.v17.i36.4067
Jin W, Dong C (2013) IL-17 cytokines in immunity and inflammation. Emerg Microbes Infect. 2. https://doi.org/10.1038/emi.2013.58
Punt S, Langenhoff JM, Putter H, Fleuren GJ, Gorter A, Jordanova ES (2015) The correlations between IL-17 vs. Th17 cells and cancer patient survival: a systematic review. Oncoimmunology 4(2):1–10. https://doi.org/10.4161/2162402X.2014.984547
Wu D, Wu P, Huang Q, Liu Y, Ye J, Huang J (2013) Interleukin-17: a promoter in colorectal cancer progression. Clin Dev Immunol. 2013:436307. https://doi.org/10.1155/2013/436307
Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, Lin Z, Zhu B (2011) IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma. Biochem Biophys Res Commun 407(2):348–354. https://doi.org/10.1016/j.bbrc.2011.03.021
Yu JJ, Gaffen SL (2008) Interleukin-17: a novel inflammatory cytokine that bridges innate and adaptive immunity. Front Biosci 13(13):170–177. https://doi.org/10.2741/2667
Gu C, Wu L, Li X (2013) Cytokine IL-17 family: cytokines, receptors and signaling. Cytokine 64(2):477–485. https://doi.org/10.1016/j.cyto.2013.07.022
Song X, Qian Y (2013) IL-17 family cytokines mediated signaling in the pathogenesis of inflammatory diseases. Cell Signal 25(12):2335–2347. https://doi.org/10.1016/j.cellsig.2013.07.021
Fabre J, Giustiniani J, Garbar C, Antonicelli F, Merrouche Y, Bensussan A, Bagot M, Al-Dacak R (2016) Targeting the tumor microenvironment: The protumor effects of IL-17 related to cancer type. Int J Mol Sci 17(9). https://doi.org/10.3390/ijms17091433
Doroudchi M, Pishe ZG, Malekzadeh M, Golmoghaddam H, Taghipour M, Ghaderi A (2013) Elevated Serum IL-17A but not IL-6 in glioma versus meningioma and schwannoma. Asian Pac J Cancer Prev 14(9):5225–5230. https://doi.org/10.7314/apjcp.2013.14.9.5225
Pan B, Shen J, Cao J, Zhou Y, Shang L, Jin S, Cao S, Che D, Liu F, Yu Y (2015) Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer. Sci Rep. 2015. https://doi.org/10.1038/srep16053
Cui G, Yuan A, Goll R, Florholmen J (2012) IL-17A in the tumor microenvironment of the human colorectal adenoma-carcinoma sequence. Scand J Gastroenterol 47(11):1304–1312. https://doi.org/10.3109/00365521.2012.725089
Steiner GE, Newman ME, Paikl D, Stix U, Memaran-Dagda N, Lee C, Marberger MJ (2003) Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate. Prostate 56(3):171–182. https://doi.org/10.1002/pros.10238
Murugaiyan G, Saha B (2009) Protumor vs antitumor functions of IL-17. J Immunol 183(7):4169–4175. https://doi.org/10.4049/jimmunol.0901017
Yang JZ, Li Y, Sun LX, Fang J, Kong LJ, Zhang JQ (2014) Interleukin-17 receptor expression on vascular endothelial cells of masses of skeletal extramedullary disease in myeloma patients. Pathol Res Pract 210(9):586–590. https://doi.org/10.1016/j.prp.2014.04.018
Ibrahim S, Girault A, Ohresser M, Lereclus E, Paintaud G, Lecomte T, Raoul W (2018) Monoclonal antibodies targeting the IL-17/IL-17RA axis: an opportunity to improve the efficiency of anti-VEGF therapy in fighting metastatic colorectal cancer? Clin Colorectal Cancer 17(1):e109–e113. https://doi.org/10.1016/j.clcc.2017.10.003
Razi S, BaradaranNoveiry B, Keshavarz-Fathi M, Rezaei N (2019) IL-17 and colorectal cancer: From carcinogenesis to treatment. Cytokine 116:7–12. https://doi.org/10.1016/j.cyto.2018.12.021
Yang B, Kang H, Fung A, Zhao H, Wang T, Ma D (2014) The role of interleukin 17 in tumour proliferation, angiogenesis, and metastasis. Mediators Inflamm. 2014:. https://doi.org/10.1155/2014/623759
Amicarella F, Muraro MG, Hirt C, Cremonesi E, Padovan E, Mele V, Governa V, Han J, Huber X, Droeser RA, Zuber M, Adamina M, Bolli M, Rosso R, Lugli A, Zlobec I, Terracciano L, Tornillo L, Zajac P, Eppenberger-Castori S, Trapani F, Oertli D, Iezzi G.(2017). Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer. 66:692–704. https://doi.org/10.1136/gutjnl-2015-310016
Wu Z, He D, Zhao S, Wang H (2019) IL-17A/IL-17RA promotes invasion and activates MMP-2 and MMP-9 expression via p38 MAPK signaling pathway in non-small cell lung cancer. 455(1–2):195–206. https://doi.org/10.1007/s11010-018-3483-9
Ernst M, Putoczki T (2014) IL-17 Cuts to the Chase in Colon Cancer. Immunity 41(6):880–882. https://doi.org/10.1016/j.immuni.2014.12.004
Moseley TA, Haudenschild DR, Rose L, Reddi AH (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14(2):155–174. https://doi.org/10.1016/S1359-6101(03)00002-9
Liu Y, Zhao X, Sun X, Li Y, Wang Z, Jiang J, Han H, Shen W, Corrigan CJ, Sun Y (2015) Expression of IL-17A, E, and F and their receptors in human prostatic cancer: comparison with benign prostatic hyperplasia. Prostate 75(16):1844–1856. https://doi.org/10.1002/pros.23058
Li YX, Zhang L, Simayi D, Zhang N, Tao L, Yang L (2015) Human papilloma virus infection correlates with inflammatory Stat3 signaling activity and IL-17 level in patients with colorectal cancer. 10(2):e0118391. https://doi.org/10.1371/journal.pone.0118391
Jiang Y, Li P, Yang S, Hao Y, Yu P (2015) Increased chemokine receptor IL-17RA expression is associated with poor survival in gastric cancer patients. 8(6):7002–7008
Wang M, Wang L, Ren T, Xu L, Wen Z (2013) IL-17A/IL-17RA interaction promoted metastasis of osteosarcoma cells. Cancer Biol Ther 14(2):155–163. https://doi.org/10.4161/cbt.22955
Yan C, Huang WY, Boudreau J, Mayavannan A, Cheng Z, Wang J (2019) IL-17R deletion predicts high-grade colorectal cancer and poor clinical outcomes. Int J Cancer 145(2):548–558. https://doi.org/10.1002/ijc.32122
Fujii T, Sutoh T, Morita H, Yajima R, Yamaguchi S, Tsutsumi S, Asao T, Kuwano H (2014) Vascular invasion, but not lymphatic invasion, of the primary tumor is a strong prognostic factor in patients with colorectal cancer. Anticancer Res 34(6):3147–3152
Xie Z, Qu Y, Leng Y, Sun W, Ma S, Wei J, Hu J, Zhang X (2015) Human colon carcinogenesis is associated with increased interleukin-17-driven inflammatory responses. Drug Des Devel Ther 9:1679–1689. https://doi.org/10.2147/DDDT.S79431
Wu D, Wu P, Huang Q, Liu Y, Ye J, Huang J (2013) Interleukin-17: a promoter in colorectal cancer progression. Clin Dev Immunol. 2013:436307. https://doi.org/10.1155/2013/436307
Tseng JY, Yang CY, Liang SC, Liu RS, Yang SH, Lin JK, Chen YM, Wu YC, Jiang JK, Lin CH (2014) Interleukin-17A modulates circulating tumor cells in tumor draining vein of colorectal cancers and affects metastases. Clin Cancer Res 20(11):2885–2897. https://doi.org/10.1158/1078-0432.CCR-13-2162
Lin Y, Xu J, Su H, Zhong W, Yuan Y, Yu Z, Fang Y, Zhou H, Li C, Huang K (2015) Interleukin-17 is a favorable prognostic marker for colorectal cancer. Clin Transl Oncol 17(1):50–56. https://doi.org/10.1007/s12094-014-1197-3
Qiu L, He D, Fan X, Li Z, Liao C, Zhu Y, Wang H (2011) The expression of interleukin (IL)-17 and IL-17 receptor and MMP-9 in human pituitary adenomas. Pituitary 14(3):266–275. https://doi.org/10.1007/s11102-011-0292-5
Rizzo A, Pallone F, Monteleone G, Fantini MC (2011) Intestinal inflammation and colorectal cancer: a double-edged sword? World J Gastroenterol. 14;17(26):3092 – 100. https://doi.org/10.3748/wjg.v17.i26.3092
Chow MT, Möller A, Smyth MJ (2012) Inflammation and immune surveillance in cancer. Semin Cancer Biol 22(1):23–32. https://doi.org/10.1016/j.semcancer.2011.12.004
Riabov V, Gudima A, Wang N, Mickley A, Orekhov A, Kzhyshkowska J (2014) Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol 5:75. https://doi.org/10.3389/fphys.2014.00075
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
These authors disclose no conflicts of interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Chai, B., Yip, W.K., Dusa, N. et al. Loss of Interleukin-17RA Expression is Associated with Tumour Progression in Colorectal Carcinoma. Pathol. Oncol. Res. 26, 2291–2298 (2020). https://doi.org/10.1007/s12253-020-00820-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12253-020-00820-4