IL‑23 concentration‑dependently regulates T24 cell proliferation, migration and invasion and is associated with prognosis in patients with bladder cancer

Wang,Peng; Zhang,Yao; Zhang,Jun; Jiang,Jun; Jin,Fengshuo; Sun,Zhongyi

doi:10.3892/or.2018.6775

IL‑23 concentration‑dependently regulates T24 cell proliferation, migration and invasion and is associated with prognosis in patients with bladder cancer

Authors:
- Peng Wang
- Yao Zhang
- Jun Zhang
- Jun Jiang
- Fengshuo Jin
- Zhongyi Sun
View Affiliations

Affiliations: Department of Urology, Daping Hospital, Institute of Surgery Research, The Third Military Medical University, Chongqing 400042, P.R. China
Published online on: October 8, 2018 https://doi.org/10.3892/or.2018.6775
Pages: 3685-3693

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Interleukin‑23 (IL‑23, also known as IL23A), is an important proinflammatory cytokine whose role in the development and progression of tumors remains controversial. The present study on IL‑23 focused on its impact on the tumor microenvironment. Existing studies on its direct role on tumor cells are limited. Previously, we reported that the expression level of IL‑23 in human bladder urothelial carcinoma was significantly higher than that in adjacent tissues as determined by immunohistochemistry. In this study, we further validated the results of immunohistochemistry using the Oncomine database and we found that IL23A expression in non‑muscle invasive bladder urothelial carcinoma (NMIBC) was significantly higher than that in muscle invasive bladder urothelial carcinoma (MIBC). Expression of IL23A was negatively correlated with the clinical stage of bladder urothelial carcinoma and had a positive correlation with prognosis. In vitro experiments revealed that different concentrations of IL‑23 had different effects on T24 cells. A low concentration of 20 ng/ml IL‑23 promoted T24 cell proliferation, migration, invasion and EMT transformation, while a high concentration of 40 ng/ml IL‑23 inhibited these functions. These results indicated that IL‑23 plays a dual role in the progression of bladder cancer. Low concentrations of IL‑23 promote bladder tumor progression, while high concentrations of IL‑23 have the opposite effect.

View Figures

View References

1	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
2	Rodriguez Martinez RH, Rueda Buisan O and Ibarz L: Bladder cancer: Present and future. Med Clin. 149:449–455. 2017.
3	Kaufman DS, Shipley WU and Feldman AS: Bladder cancer. Lancet. 374:239–249. 2009. View Article : Google Scholar : PubMed/NCBI
4	Thompson DB, Siref LE, Feloney MP, Hauke RJ and Agrawal DK: Immunological basis in the pathogenesis and treatment of bladder cancer. Expert Rev Clin Immunol. 11:265–279. 2015. View Article : Google Scholar : PubMed/NCBI
5	Croxford AL, Mair F and Becher B: IL-23: One cytokine in control of autoimmunity. Eur J Immunol. 42:2263–2273. 2012. View Article : Google Scholar : PubMed/NCBI
6	Wang P, Yang B, Zhou B, Zhang J, Li S, Jiang J, Sun Z and Jin F: Distribution and expression profiles of dendritic cell subpopulations in human bladder cancer. Int J Clin Exp Pathol. 9:7180–7187. 2016.
7	Segura E, Touzot M, Bohineust A, Cappuccio A, Chiocchia G, Hosmalin A, Dalod M, Soumelis V and Amigorena S: Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity. 38:336–348. 2013. View Article : Google Scholar : PubMed/NCBI
8	Croxford AL, Kulig P and Becher B: IL-12-and IL-23 in health and disease. Cytokine Growth Factor Rev. 25:415–421. 2014. View Article : Google Scholar : PubMed/NCBI
9	Gagliani N, Hu B, Huber S, Elinav E and Flavell RA: The fire within: Microbes inflame tumors. Cell. 157:776–783. 2014. View Article : Google Scholar : PubMed/NCBI
10	Tugues S, Burkhard SH, Ohs I, Vrohlings M, Nussbaum K, Berg Vom J, Kulig P and Becher B: New insights into IL-12-mediated tumor suppression. Cell Death Differ. 22:237–246. 2015. View Article : Google Scholar : PubMed/NCBI
11	Wang K and Karin M: The IL-23 to IL-17 cascade inflammation-related cancers. Clin Exp Rheumatol. 33 4 Suppl 92:S87–S90. 2015.PubMed/NCBI
12	Teng MW, Andrews DM, McLaughlin N, von Scheidt B, Ngiow SF, Möller A, Hill GR, Iwakura Y, Oft M and Smyth MJ: IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis. Proc Natl Acad Sci USA. 107:8328–8333. 2010. View Article : Google Scholar : PubMed/NCBI
13	Sobin L, Gospodarowicz M and Wittekind C: TNM classification of malignant tumors., in U1CC 1nternational Union Against Cancer. Wiley-Blackwell. 262–265. 2009.
14	Kindelan Alvarez J, Campos Hernández JP, López Beltrán A and Requena Tapia MJ: The 2004 WHO classification of bladder tumors: A summary and commentary. Actas Urol Esp. 31:978–988. 2007.(In Spanish). PubMed/NCBI
15	Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI
16	Cancer Genome Atlas Research Network: Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 507:315–522. 2014. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Qian X, Gu L, Ning H, Zhang Y, Hsueh EC, Fu M, Hu X, Wei L, Hoft DF and Liu J: Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2. J Immunol. 190:5894–5902. 2013. View Article : Google Scholar : PubMed/NCBI
19	Lee JS, Leem SH, Lee SY, Kim SC, Park ES, Kim SB, Kim SK, Kim YJ, Kim WJ and Chu IS: Expression signature of E2F1 and its associated genes predict superficial to invasive progression of bladder tumors. J Clin Oncol. 28:2660–2667. 2010. View Article : Google Scholar : PubMed/NCBI
20	Sanchez-Carbayo M, Socci ND, Lozano J, Saint F and Cordon-Cardo C: Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol. 24:778–789. 2006. View Article : Google Scholar : PubMed/NCBI
21	Cancer Genome Atlas Research, Network: Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 455:1061–1068. 2008. View Article : Google Scholar : PubMed/NCBI
22	Singh M, Yelle N, Venugopal C and Singh SK: EMT: Mechanisms and therapeutic implications. Pharmacol Ther. 182:80–94. 2018. View Article : Google Scholar : PubMed/NCBI
23	Dominguez C, David JM and Palena C: Epithelial-mesenchymal transition and inflammation at the site of the primary tumor. Semin Cancer Biol. 47:177–184. 2017. View Article : Google Scholar : PubMed/NCBI
24	Kanda Y, Osaki M and Okada F: Chemopreventive strategies for inflammation-related carcinogenesis: Current status and future direction. Int J Mol Sci. 18:pii: E8672017. View Article : Google Scholar
25	Ngiow SF, Teng MW and Smyth MJ: A balance of interleukin-12 and −23 in cancer. Trends Immunol. 34:548–555. 2013. View Article : Google Scholar : PubMed/NCBI
26	Langowski JL, Kastelein RA and Oft M: Swords into plowshares: IL-23 repurposes tumor immune surveillance. Trends Immunol. 28:207–212. 2007. View Article : Google Scholar : PubMed/NCBI
27	Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA and Oft M: IL-23 promotes tumour incidence and growth. Nature. 442:461–465. 2006. View Article : Google Scholar : PubMed/NCBI
28	Chugh S, Anand V, Swaroop L, Sharma M, Seth A and Sharma A: Involvement of Th17 cells in patients of urothelial carcinoma of bladder. Hum Immunol. 74:1258–1262. 2013. View Article : Google Scholar : PubMed/NCBI
29	Li J, Lau G, Chen L, Yuan YF, Huang J, Luk JM, Xie D and Guan XY: Interleukin 23 promotes hepatocellular carcinoma metastasis via NF-kappa B induced matrix metalloproteinase 9 expression. PLoS One. 7:e462642012. View Article : Google Scholar : PubMed/NCBI
30	Fukuda M, Ehara M, Suzuki S, Ohmori Y and Sakashita H: IL-23 promotes growth and proliferation in human squamous cell carcinoma of the oral cavity. Int J Oncol. 36:1355–1365. 2010. View Article : Google Scholar : PubMed/NCBI
31	Hu P, Hu HD, Chen M, Peng ML, Tang L, Tang KF, Matsui M, Belladonna ML, Yoshimoto T, Zhang DZ, et al: Expression of interleukins-23 and 27 leads to successful gene therapy of hepatocellular carcinoma. Mol Immunol. 46:1654–1662. 2009. View Article : Google Scholar : PubMed/NCBI
32	Reay J, Gambotto A and Robbins PD: The antitumor effects of adenoviral-mediated, intratumoral delivery of interleukin 23 require endogenous IL-12. Cancer Gene Ther. 19:135–143. 2012. View Article : Google Scholar : PubMed/NCBI
33	Jin HT, Youn JI, Choi SY, Seo SH, Park SH, Song MY, Yang SH and Sung YC: Adenovirus-mediated gene transfer of interleukin-23 shows prophylactic but not therapeutic antitumor effects. Cancer Gene Ther. 15:693–702. 2008. View Article : Google Scholar : PubMed/NCBI
34	von Scheidt B, Leung PS, Yong MC, Zhang Y, Towne JE, Smyth MJ and Teng MW: Combined anti-CD40 and anti-IL-23 monoclonal antibody therapy effectively suppresses tumor growth and metastases. Cancer Res. 74:2412–2421. 2014. View Article : Google Scholar : PubMed/NCBI
35	Li J, Zhang L, Zhang J, Wei Y, Li K, Huang L, Zhang S, Gao B, Wang X and Lin P: Interleukin 23 regulates proliferation of lung cancer cells in a concentration-dependent way in association with the interleukin-23 receptor. Carcinogenesis. 34:658–666. 2013. View Article : Google Scholar : PubMed/NCBI
36	Kortylewski M, Xin H, Kujawski M, Lee H, Liu Y, Harris T, Drake C, Pardoll D and Yu H: Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell. 15:114–123. 2009. View Article : Google Scholar : PubMed/NCBI
37	Stewart CA and Trinchieri G: Reinforcing suppression using regulators: A new link between STAT3, IL-23, and Tregs in tumor immunosuppression. Cancer Cell. 15:81–83. 2009. View Article : Google Scholar : PubMed/NCBI