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Medical Oncology

, 34:23 | Cite as

IL-33 acts as a foe to MIA PaCa-2 pancreatic cancer

  • Yujiang FangEmail author
  • Lei Zhao
  • Huaping Xiao
  • Kathryn M. Cook
  • Qian Bai
  • Elizabeth J. Herrick
  • Xuhui Chen
  • Chenglu Qin
  • Ziwen Zhu
  • Mark R. Wakefield
  • Michael B. Nicholl
Original Paper

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.

Keywords

IL-33 Apoptosis Proliferation 

Notes

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.

Compliance with ethical standards

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.

References

  1. 1.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605–17.CrossRefPubMedGoogle Scholar
  3. 3.
    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.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    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.CrossRefPubMedGoogle Scholar
  6. 6.
    Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 2009;6(12):699–708.CrossRefPubMedGoogle Scholar
  7. 7.
    Saif MW. Pancreatic neoplasm in 2011: an update. JOP. 2011;12(4):316–21.PubMedGoogle Scholar
  8. 8.
    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.CrossRefPubMedGoogle Scholar
  9. 9.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.CrossRefPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedGoogle Scholar
  11. 11.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607–20.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov. 2008;7(10):827–40.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Miller AM. Role of IL-33 in inflammation and disease. J Inflamm (Lond). 2011;8(1):22.CrossRefGoogle Scholar
  17. 17.
    Palmer G, Gabay C. Interleukin-33 biology with potential insights into human diseases. Nat Rev Rheumatol. 2011;7(6):321–9.CrossRefPubMedGoogle Scholar
  18. 18.
    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.CrossRefPubMedGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefPubMedGoogle Scholar
  22. 22.
    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.CrossRefPubMedGoogle Scholar
  23. 23.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    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.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    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.CrossRefPubMedGoogle Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    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.CrossRefPubMedGoogle Scholar
  31. 31.
    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.CrossRefPubMedGoogle Scholar
  32. 32.
    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.CrossRefPubMedGoogle Scholar
  33. 33.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    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.
  36. 36.
    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.CrossRefPubMedGoogle Scholar
  37. 37.
    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.CrossRefPubMedGoogle Scholar
  38. 38.
    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.CrossRefPubMedGoogle Scholar
  39. 39.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Johnson D, Walker C. Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol. 1999;39(1):295–312.CrossRefPubMedGoogle Scholar
  43. 43.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Sherr CJ. G1 phase progression: cycling on cue. Cell. 1994;79(4):551–5.CrossRefPubMedGoogle Scholar
  45. 45.
    Sherr CJ. D-type cyclins. Trends Biochem Sci. 1995;20(5):187–90.CrossRefPubMedGoogle Scholar
  46. 46.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    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.CrossRefPubMedGoogle Scholar
  49. 49.
    Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267(5203):1456.CrossRefPubMedGoogle Scholar
  50. 50.
    Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Yujiang Fang
    • 1
    • 2
    Email author
  • Lei Zhao
    • 3
  • Huaping Xiao
    • 1
    • 5
  • Kathryn M. Cook
    • 2
  • Qian Bai
    • 2
  • Elizabeth J. Herrick
    • 2
  • Xuhui Chen
    • 1
    • 6
  • Chenglu Qin
    • 2
    • 6
  • Ziwen Zhu
    • 2
  • Mark R. Wakefield
    • 2
  • Michael B. Nicholl
    • 2
    • 4
  1. 1.Department of Microbiology, Immunology and Pathology, College of Osteopathic MedicineDes Moines UniversityDes MoinesUSA
  2. 2.Department of SurgeryUniversity of Missouri School of MedicineColumbiaUSA
  3. 3.Department of Infectious DiseaseThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
  4. 4.Department of SurgerySouth Texas Veterans Health Care SystemSan AntonioUSA
  5. 5.The Affiliated Hospital of Xiangnan UniversityChenzhouChina
  6. 6.Luohu HospitalShenzhenChina

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