Abstract
IL-33 is a member of the IL-1 family of cytokines, and no study has been performed to address its direct anti-tumor effect. This study is designed to investigate whether IL-33 has any direct effect on pancreatic cancer. Clonogenic survival assay, immunohistochemistry, TUNEL staining, proliferation, caspase-3 activity kits and RT-PCR were used to evaluate the effects of IL-33 on cell survival, proliferation and apoptosis of a pancreatic cancer cell line, MIA PaCa-2. We found that the percentage of colonies of MIA PaCa-2 cells, PCNA+ cells and the OD value of cancer cells were all decreased in the presence of IL-33. TUNEL+ cells and the relative caspase-3 activity in cancer cells were increased in the presence of IL-33. We further found that its anti-proliferative effect on cancer cells correlated with downregulation of pro-proliferative molecules cdk2 and cdk4 and upregulation of anti-proliferative molecules p15, p21 and p53. Its pro-apoptotic effect correlated with downregulation of anti-apoptotic molecule FLIP and upregulation of pro-apoptotic molecule TRAIL. These results suggest that IL-33 presents significant anti-tumor effects by inhibition of proliferation and induction of apoptosis of MIA PaCa-2 pancreatic cancer cells. Thus, strength of IL-33/ST2 signal pathway might be a promising way to treat pancreatic cancer.
Similar content being viewed by others
References
Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2016;30(4):355–85.
Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605–17.
Kim J, Kim W, Kim HJ, Choi H-J, Cho H, Kwon B. PS2-077 Association of inhibition of tumor growth with intratumoral hematopoiesis induced by IL-33. Cytokine. 2011;56(1):85.
Mahmood A, McSharry C, Xu D, Peacock A, Welsh D. S155 The role of ST2 in a model of pulmonary hypertension. Thorax. 2010;65(Suppl 4):A70–1.
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.
Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 2009;6(12):699–708.
Saif MW. Pancreatic neoplasm in 2011: an update. JOP. 2011;12(4):316–21.
Saleh H, Eeles D, Hodge JM, Nicholson GC, Gu R, Pompolo S, et al. Interleukin-33, a target of parathyroid hormone and oncostatin m, increases osteoblastic matrix mineral deposition and inhibits osteoclast formation in vitro. Endocrinology. 2011;152(5):1911–22.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.
Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, et al. Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol. 2011;8(1):27–33.
Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, et al. Recent progress in pancreatic cancer. CA Cancer J Clin. 2013;63(5):318–48.
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607–20.
Porta C, Paglino C, Imarisio I, Bonomi L. Cytokine-based immunotherapy for advanced kidney cancer: past results and future perspectives in the era of molecularly targeted agents. Sci World J. 2007;7:837–49.
Coyle AJ, Lloyd C, Tian J, Nguyen T, Erikkson C, Wang L, et al. Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2–mediated lung mucosal immune responses. J Exp Med. 1999;190(7):895–902.
Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov. 2008;7(10):827–40.
Miller AM. Role of IL-33 in inflammation and disease. J Inflamm (Lond). 2011;8(1):22.
Palmer G, Gabay C. Interleukin-33 biology with potential insights into human diseases. Nat Rev Rheumatol. 2011;7(6):321–9.
Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23(5):479–90.
Alves-Filho JC, Sônego F, Souto FO, Freitas A, Verri WA Jr, Auxiliadora-Martins M, et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat Med. 2010;16(6):708–12.
Humphreys NE, Xu D, Hepworth MR, Liew FY, Grencis RK. IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J Immunol. 2008;180(4):2443–9.
Kondo Y, Yoshimoto T, Yasuda K, Futatsugi-Yumikura S, Morimoto M, Hayashi N, et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol. 2008;20(6):791–800.
Leung BP, Xu D, Culshaw S, McInnes IB, Liew FY. A novel therapy of murine collagen-induced arthritis with soluble T1/ST2. J Immunol. 2004;173(1):145–50.
Townsend MJ, Fallon PG, Matthews DJ, Jolin HE, McKenzie AN. T1/ST2-deficient mice demonstrate the importance of T1/ST2 in developing primary T helper cell type 2 responses. J Exp Med. 2000;191(6):1069–76.
Verri WA, Guerrero AT, Fukada SY, Valerio DA, Cunha TM, Xu D, et al. IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice. Proc Natl Acad Sci. 2008;105(7):2723–8.
Wieland CW, van der Windt GJ, Florquin S, McKenzie AN, van der Poll T. ST2 deficient mice display a normal host defense against pulmonary infection with Mycobacterium tuberculosis. Microbes Infect. 2009;11(4):524–30.
Xu D, Jiang H-R, Kewin P, Li Y, Mu R, Fraser AR, et al. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc Natl Acad Sci. 2008;105(31):10913–8.
Zhiguang X, Wei C, Steven R, Wei D, Wei Z, Rong M, et al. Over-expression of IL-33 leads to spontaneous pulmonary inflammation in mIL-33 transgenic mice. Immunol Lett. 2010;131(2):159–65.
Gao X, Wang X, Yang Q, Zhao X, Wen W, Li G, et al. Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells. J Immunol. 2015;194(1):438–45.
Jovanovic I, Radosavljevic G, Mitrovic M, Lisnic Juranic V, McKenzie AN, Arsenijevic N, et al. ST2 deletion enhances innate and acquired immunity to murine mammary carcinoma. Eur J Immunol. 2011;41(7):1902–12.
Kim J, Lim S, Kim G, Yun H, Ahn S, Choi H. Interleukin-33/ST2 axis promotes epithelial cell transformation and breast tumorigenesis via upregulation of COT activity. Oncogene. 2014;34:4928–38.
Kim MS, Kim E, Heo J-S, Bae D-J, Lee J-UW, Lee T-H, et al. Circulating IL-33 level is associated with the progression of lung cancer. Lung Cancer. 2015;90(2):346–51.
Liu X, Zhu L, Lu X, Bian H, Wu X, Yang W, et al. IL-33/ST2 pathway contributes to metastasis of human colorectal cancer. Biochem Biophys Res Commun. 2014;453(3):486–92.
Maywald RL, Doerner SK, Pastorelli L, De Salvo C, Benton SM, Dawson EP, et al. IL-33 activates tumor stroma to promote intestinal polyposis. Proc Natl Acad Sci. 2015;112(19):E2487–96.
Yamada D, Rizvi S, Razumilava N, Bronk SF, Davila JI, Champion MD, et al. IL-33 facilitates oncogene-induced cholangiocarcinoma in mice by an interleukin-6-sensitive mechanism. Hepatology. 2015;61(5):1627–42.
Yang Z-P, Ling D-Y, Xie Y-H, Wu W-X, Li J-R, Jiang J et al. The association of serum IL-33 and sST2 with breast cancer. Dis Markers. 2015. doi:10.1155/2015/516895.
Yu X-X, Hu Z, Shen X, Dong L-Y, Zhou W-Z, Hu W-H. IL-33 promotes gastric cancer cell invasion and migration via ST2–ERK1/2 pathway. Dig Dis Sci. 2015;60(5):1265–72.
Fang Y, Chen X, Bai Q, Qin C, Mohamud AO, Zhu Z, et al. IL-9 inhibits HTB-72 melanoma cell growth through upregulation of p21 and TRAIL. J Surg Oncol. 2015;111(8):969–74.
Fang Y, DeMarco VG, Nicholl MB. Resveratrol enhances radiation sensitivity in prostate cancer by inhibiting cell proliferation and promoting cell senescence and apoptosis. Cancer Sci. 2012;103(6):1090–8.
Fang Y, Yu S, Braley-Mullen H. TGF-β promotes proliferation of thyroid epithelial cells in IFN-γ−/− mice by down-regulation of p21 and p27 via AKT pathway. Am J Pathol. 2012;180(2):650–60.
Fang Y, Sharp GC, Yagita H, Braley-Mullen H. A critical role for TRAIL in resolution of granulomatous experimental autoimmune thyroiditis. J Pathol. 2008;216(4):505–13.
Fang Y, Wei Y, DeMarco V, Chen K, Sharp GC, Braley-Mullen H. Murine FLIP transgene expressed on thyroid epithelial cells promotes resolution of granulomatous experimental autoimmune thyroiditis in DBA/1 mice. Am J Pathol. 2007;170(3):875–87.
Johnson D, Walker C. Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol. 1999;39(1):295–312.
Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol. 1995;15(5):2612–24.
Sherr CJ. G1 phase progression: cycling on cue. Cell. 1994;79(4):551–5.
Sherr CJ. D-type cyclins. Trends Biochem Sci. 1995;20(5):187–90.
Zhang D, Li X, Chen C, Li Y, Zhao L, Jing Y, et al. Attenuation of p38-mediated miR-1/133 expression facilitates myoblast proliferation during the early stage of muscle regeneration. PLoS ONE. 2012;7(7):e41478.
Fang Y, Braley-Mullen H. Cultured murine thyroid epithelial cells expressing transgenic Fas-associated death domain-like interleukin-1β converting enzyme inhibitory protein are protected from Fas-mediated apoptosis. Endocrinology. 2008;149(7):3321–9.
Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science. 1995;270(5239):1189–92.
Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267(5203):1456.
Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.
Acknowledgement
We thank Mr. Tyler W. Ball for his help for revision of this manuscript.
Funding
This study was partially supported by grants from Des Moines University for Yujiang Fang (Iowa Science Foundation Grant ISF 16-8, IOER 05-14-01, IOER 112-3749 and IOER 112-3104). This study was also supported by a grant from University of Missouri for Michael B. Nicholl and Yujiang Fang.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Rights and permissions
About this article
Cite this article
Fang, Y., Zhao, L., Xiao, H. et al. IL-33 acts as a foe to MIA PaCa-2 pancreatic cancer. Med Oncol 34, 23 (2017). https://doi.org/10.1007/s12032-016-0880-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12032-016-0880-3