Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605–17.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  6. Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 2009;6(12):699–708.

    Article  PubMed  Google Scholar 

  7. Saif MW. Pancreatic neoplasm in 2011: an update. JOP. 2011;12(4):316–21.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  9. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607–20.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov. 2008;7(10):827–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Miller AM. Role of IL-33 in inflammation and disease. J Inflamm (Lond). 2011;8(1):22.

    Article  CAS  Google Scholar 

  17. Palmer G, Gabay C. Interleukin-33 biology with potential insights into human diseases. Nat Rev Rheumatol. 2011;7(6):321–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Johnson D, Walker C. Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol. 1999;39(1):295–312.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sherr CJ. G1 phase progression: cycling on cue. Cell. 1994;79(4):551–5.

    Article  CAS  PubMed  Google Scholar 

  45. Sherr CJ. D-type cyclins. Trends Biochem Sci. 1995;20(5):187–90.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  49. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267(5203):1456.

    Article  CAS  PubMed  Google Scholar 

  50. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.

    Article  CAS  PubMed  Google Scholar 

Download references

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

  1. Department of Microbiology, Immunology and Pathology, College of Osteopathic Medicine, Des Moines University, Des Moines, IA, 50312, USA

    Yujiang Fang, Huaping Xiao & Xuhui Chen

  2. Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA

    Yujiang Fang, Kathryn M. Cook, Qian Bai, Elizabeth J. Herrick, Chenglu Qin, Ziwen Zhu, Mark R. Wakefield & Michael B. Nicholl

  3. Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

    Lei Zhao

  4. Department of Surgery, South Texas Veterans Health Care System, 7400 Merton Minter Blvd, San Antonio, TX, 78229, USA

    Michael B. Nicholl

  5. The Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, China

    Huaping Xiao

  6. Luohu Hospital, Shenzhen, China

    Xuhui Chen & Chenglu Qin

Authors
  1. Yujiang Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huaping Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kathryn M. Cook
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qian Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elizabeth J. Herrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xuhui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chenglu Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ziwen Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark R. Wakefield
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael B. Nicholl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yujiang Fang.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-016-0880-3

Keywords

Search

Navigation