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High expression of Foxp3, IL-23p19 and survivin mRNA in colorectal carcinoma

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Introduction

Cytokines have been suggested to both modulate anti-tumor responses and promote tumor growth.

Materials and methods

We analyzed the expression of pro-inflammatory IL-12p35, IL-12p40, IL-23p19, anti-inflammatory IL-10, antiapoptotic factor survivin, and transcription factors—RelA, c-Jun, and Foxp3 mRNA in patients’ blood, colon carcinoma tissue, and in normal mucosal tissue by real-time polymerase chain reaction. The quantity determination of serum IL-12p40, IL-23, and IL-10 was performed by enzyme-linked immunosorbent assay.

Results

We observed significantly higher levels in patients for all three analyzed cytokines, with IL-23 concentration change being the highest. We detected the greatest upregulation of IL-23p19, Foxp3 and survivin mRNA in colorectal carcinomas than normal mucosa. A statistically significant upregulation of IL-12p40, IL-10, and c-Jun mRNA but not for IL-12p35 and RelA mRNA in tumor tissue comparing to normal tissue was also established.

Conclusions

In conclusion, we show a characteristic gene expression profile combining markers associated with inhibition of anti-tumor immune response (Foxp3, IL-10), inhibition of apoptosis (survivin), and induction of the cytokines with protumoral activity as IL-12p40 and IL-23p19 (IL-23) in the colorectal tumor tissue but not in peripheral blood of patients.

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References

  1. Balkwill F, Mantovani A (2001) Inflamation and cancer: back to virchow? Lancet 357:539–545

    Article  PubMed  CAS  Google Scholar 

  2. Coussens LM, Werb Z (2002) Inflamation and cancer. Nature 420:860–867

    Article  PubMed  CAS  Google Scholar 

  3. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148

    Article  PubMed  CAS  Google Scholar 

  4. Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nature Reviews 4:11–22

    Article  PubMed  CAS  Google Scholar 

  5. Bellone G, Smirne C, Mauri F, Tonel E, Carbone A, Buffolino A, Dughera L, Robecchi A, Pirsi M, Emanuelli G (2006) Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: implication for survival. Cancer Immunol Immunother 55:684–698

    Article  PubMed  CAS  Google Scholar 

  6. Brunda MJ, Luistro L, Hendzak JA, Fountoulakis M, Garotta G, Gately MK (1995) Role of interferon-γ in mediating the antitumor efficacy of interleukin-12. J Immunother Emphas Tumor Immunol 17:71–77

    CAS  Google Scholar 

  7. Gri G, Chiodoni C, Gallo E, Stoppacciaro A, Liew F, Colombo M (2002) Antitumor effect of Interleukin (IL)-12 in the absence of endogeneous IFN-γ: a role for intrinsic tumor immunogenicity and IL-15. Cancer Research 62:4390–4397

    PubMed  CAS  Google Scholar 

  8. Hölscher C (2004) The power of combinatorial immunology: IL-12 and IL-12-related dimeric cytokines in infectious diseases. Med Microbiol Immunol 193:1–17

    Article  PubMed  CAS  Google Scholar 

  9. Kawamura K, Bahar R, Natsume W, Sakiyama S, Tagawa M (2002) Secretion of interleukin-10 from murine colon carcinoma cells suppresses systemic antitumor immunity and impairs protective immunity against tumors. Cancer Gene Therapy 9:109–115

    Article  PubMed  CAS  Google Scholar 

  10. Cui G, Goll R, Olsen T, Steigen SE, Husebekk A, Vonen B, Florholmen J (2007) Reduced expression of microenvironmental Th1 cytokines accompanies adenomas-carcinomas sequence of colorectum. Cancer Immunol Immunother 56:985–995

    Article  PubMed  CAS  Google Scholar 

  11. O’Hara RJ, Greenman J, MacDonald AW, Gaskell KM, Topping KP, Duthie GS, Kerin MJ, Lee PW, Monson JR (1998) Advansed colorectal cancer is associated with impared interleukin 12 and enhanced interleukin 10 production. Clin Cancer Res 4:1943–1948

    PubMed  CAS  Google Scholar 

  12. Dalerba P, Maccalli C, Casati C, Castelli C, parmiani G (2003) Immunology and immunotherapy of colorectal cancer. Crit Rev Oncol Hematol 46:33–57

    Article  PubMed  Google Scholar 

  13. Zhang W, Hart J, McLeod H, Pharm D, Wang H (2005) Differential expression of the AP-1 transcription factor family members in human colorectal epithelial and neurondocrine neoplasm. Am J Clin Pathol 124:11–19

    Article  PubMed  CAS  Google Scholar 

  14. Young MR, Yang HS, Colburn NH (2003) Promising molecular targets for cancer prevention: AP-1, NF-kB and Pdcd4. Trends Mol Med 9:36–41

    Article  PubMed  CAS  Google Scholar 

  15. Ashida R, Tominaga K, Sasaki E, Watanabe T, Fujiwara Y, Oshitani N, Higuchi K, Mitsuyama S, Iwao H, Arakawa T (2005) AP-1 and colorectal cancer. Immunopharmacology 13:113–125

    CAS  Google Scholar 

  16. Murphy L, Cleveland M, Kulesza P, Magram J, Murphy K (1995) Regulation of interleukin 12 p40 expression through an NF-kB half-site. Mol Cell Biol 15:5258–5267

    PubMed  CAS  Google Scholar 

  17. Blackwell S, Christmas J (1997) The role of nuclear factor-kB in cytokine gene regulation. Am J Respir Cell Mol Biol 17:3–9

    PubMed  CAS  Google Scholar 

  18. Yagi H, Nomura T, Nakamura K, Yamazaki S, Kitawaki T, Hori S et al (2004) Crucial role of foxp3 in the development and function of human CD25 + CD4 + regulatory T cells. International Immunology 16:1643–1656

    Article  PubMed  CAS  Google Scholar 

  19. Zheng Y, Rudensky A (2007) Foxp3 in control of the regulatory T cell lineage. Nature Immunology 8:457–462

    Article  PubMed  CAS  Google Scholar 

  20. Jarnicki A, Lysaght J, Todryk S, Mills K (2006) Suppression of antitumor immunity by IL-10 and TGF-β-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4 + and CD8 + regulatory T cells. J Immunol 177:896–904

    PubMed  CAS  Google Scholar 

  21. Andersen MH, Svane IM, Becker JC, Straten PT (2007) The universal character of the tumor-associated antigen survivin. Clin Cancer Res 13:5991–5994

    Article  PubMed  CAS  Google Scholar 

  22. Baier PK, Wolff-Vorbeck G, Eggstein S, Baumgartner U, Hopt UT (2005) Cytokine expression in colon carcinoma. Anticancer Research 25:2135–2140

    PubMed  CAS  Google Scholar 

  23. Dobreva Z, Stanilova S, Miteva L (2008) Differences in the inducible gene expression and protein production of IL-12p40, IL-12p70 and IL-23: involvement of p38 and JNK kinase pathways. Cytokine 43:76–82

    Article  PubMed  CAS  Google Scholar 

  24. Endo T, Abe S, Seidlar HB, Nagaoka S, Takemura T, Utsuyama M, Kitagawa M, Hirokawa K (2004) Expression of IAP family proteins in colon cancers from patients with different age groups. Cancer Immunol Immunother 53:770–776

    Article  PubMed  CAS  Google Scholar 

  25. Wang YQ, Ugai S, Shimozato O, Yu L, Kawamura K, Yamamoto H, Yamaguchi T, Saisho H, Tagawa M (2003) Induction of systemic immunity by expression of interleukin-23 in murine colon carcinoma cells. Int J Cancer 105:820–824

    Article  PubMed  CAS  Google Scholar 

  26. Lo CH, Lee SC, Wu PY, Pan WY, Su J, Cheng CW, Roffler SR, Chiang BL, Lee CN, Wu CW, Tao MH (2003) Antitumor and antimetastatic activity of IL-23. J Immunol 171:600–607

    PubMed  CAS  Google Scholar 

  27. Shan B, Hao J, Li Q, Tagawa M (2006) Antitumor activity and immune enhancement of murine interleukin-23 expressed in murine colon carcinoma cells. Cell Mol Immunol 3:47–52

    PubMed  CAS  Google Scholar 

  28. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanaham T, Kastelein R, Oft M (2006) IL-23 promotes tumor incidence and growth. Nature 442:461–465

    Article  PubMed  CAS  Google Scholar 

  29. Ling P, Gately MK, Gubler U, Stern AS, Lin P, Hollfelder K, Su C, Pan YC, Hakimi J (1995) Human IL-12p40 homodimer binds to the Il-12 receptor but does not mediate biologic activity. J Immunol 154:116–127

    PubMed  CAS  Google Scholar 

  30. Wang Z, Sato H, Kusam S, Sehra S, Toney L, Dent A (2005) Regulation of IL-10 gene expression in Th2 cells by Jun proteins. J Immunol 174:2098–2105

    PubMed  CAS  Google Scholar 

  31. Aggarwal BB (2004) Nuclear factor-kappaB: the enemy within. Cancer Cell 6:203–208

    Article  PubMed  CAS  Google Scholar 

  32. Yu LL, Yu HG, Yu JP, Luo HS, Xu XM, Li JH (2004) Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human colorectal carcinoma tissue. World J Gastroenterol 10:3255–3260

    PubMed  CAS  Google Scholar 

  33. Le Gouvello S, Bastuji-Garin S, Aloulou N, Mansour H, Chaumette T, Berrehar F, Seikour A, Charachon A, Karoui M, Leroy K, Farcet J-P, Sobhani I (2008) High prevalence of Foxp3 and IL-17 in MMR-proficient colorectal carcinomas. Gut 57:772–779

    Article  PubMed  Google Scholar 

  34. Karanikas V, Speletes M, Zamanakou M, Kalala F, Loules G, Karenidi T, barda A, Gourgoulianis K, Germenis A (2008) Foxp3 expression in human cancer cells. J Transl Med 6:19–30

    Article  PubMed  CAS  Google Scholar 

  35. Ebert LM, Tan BS, Browning J, Svobodova S, Russell SE, Kirkpatrick N, Gedye C, Moss D, Ng SP, MacGregor D, Davis ID, Cebon J, Chen W (2008) The regulatory T-cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res 68:3001–3009

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This work was supported by Grant N: 4/2008 from the Fund for Scientific and Mobile project from Faculty of Medicine at the Trakia University-Stara Zagora, Bulgaria.

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Correspondence to Spaska Stanilova.

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Stanilov, N., Miteva, L., Mintchev, N. et al. High expression of Foxp3, IL-23p19 and survivin mRNA in colorectal carcinoma. Int J Colorectal Dis 24, 151–157 (2009). https://doi.org/10.1007/s00384-008-0588-8

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  • DOI: https://doi.org/10.1007/s00384-008-0588-8

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