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Macrophage migration inhibitory factor expression in cervical cancer

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Abstract

Purpose

The glycoprotein macrophage migration inhibitory factor (MIF) is a cytokine that has been shown to promote tumor progression and tumor immune escape in ovarian cancer. The present study investigates MIF in uterine cervical cancer.

Methods

Eighty surgical biopsies (32 cervical dysplasias, 23 in situ carcinomas and 25 invasive carcinomas) of uterine cervical tissue were evaluated immunohistochemically for MIF expression. In uterine cervical cancer cell lines SiHa and CaSki and their respective supernatants, MIF protein expression was analyzed by Western blotting, enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR).

Results

Immunohistochemical analysis shows that MIF is clearly overexpressed on the protein level in invasive cervical cancer compared to cervical dysplasias. MIF overexpression was confirmed by RT-PCR in surgical biopsies of invasive cervical cancer. Western blotting reveals that the MIF protein is overexpressed in SiHA und CaSki cervical cancer cell lines, whereas the ELISA reveals that cervical cancer cells secrete MIF.

Conclusions

MIF has been shown to promote tumor immune escape mechanisms in other cancer entities, which makes it an interesting target for cancer therapy, given the known significance of immune mechanisms for uterine cervical cancer. The overexpression of MIF on the protein and mRNA level, as well as its secretion by cervical cancer cells points to a critical role of the protein for the pathogenesis of uterine cervical cancer.

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References

  • Agarwal R, Whang DH, Alvero AB Visintin I, Lai Y, Segal EA, Schwartz P, Ward D, Rutherford T, Mor G (2007) Macrophage migration inhibitory factor expression in ovarian cancer. Am J Obstet Gynecol 196:348.e1-e5

    Google Scholar 

  • Bartfeld H, Atoynatan T (1971) Activity and properties of macrophage migration inhibitory factor produced by mixed lymphocyte cultures. Nat New Biol 230(16):246–247

    CAS  PubMed  Google Scholar 

  • Binsky I, Haran M, Starlets D, Gore Y, Lantner F, Harpaz N, Leng L, Goldenberg DM, Shvidel L, Berrebi A, Bucala R, Shachar I (2007) IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival. Proc Natl Acad Sci USA 104:13408–13413

    Article  CAS  PubMed  Google Scholar 

  • Camlica H, Duranyildiz D, Oguz H, Oral EN, Yasasever V (2008) The diagnostic value of macrophage migration inhibitory factor (MIF) in gastric cancer. Pathol Oncol Res 14:79–83

    Article  CAS  PubMed  Google Scholar 

  • Coleman AM, Rendon BE, Zhao M, Qian MW, Bucala R, Xin D, Mitchell RA (2008) Cooperative regulation of non-small cell lung carcinoma angiogenic potential by macrophage migration inhibitory factor and its homolog, d-dopachrome tautomerase. J Immunol 181:2330–2337

    CAS  PubMed  Google Scholar 

  • Fingerle-Rowson G, Petrenko O, Metz CN, Forsthuber TG, Mitchell R, Huss R, Moll U, Müller W, Bucala R (2003) The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc Natl Acad Sci USA 100:9354–9359

    Article  CAS  PubMed  Google Scholar 

  • Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, Charles K, Klemm F, Pukrop T, Binder C, Balkwill FR (2005) Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol 175:1197–1205

    CAS  PubMed  Google Scholar 

  • James RM, Cruickshank ME, Siddiqui N (2008) Guideline Development Group. Management of cervical cancer: summary of SIGN guidelines. BMJ 336:41–43

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics. CA Cancer J Clin 58:71–96

    Article  PubMed  Google Scholar 

  • Krockenberger M, Dombrowski Y, Weidler C, Ossadnik M, Hönig A, Häusler S, Voigt H, Becker JC, Leng L, Steinle A, Weller M, Bucala R, Dietl J, Wischhusen J (2008) Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D. J Immunol 180:7338–7348

    CAS  PubMed  Google Scholar 

  • Lee H, Rhee H, Kang HJ, Kim HS, Min BS, Kim NK, Kim H (2008) Macrophage migration inhibitory factor may be used as an early diagnostic marker in colorectal carcinomas. Am J Clin Pathol 129:772–779

    Article  PubMed  Google Scholar 

  • Long HJ 3rd (2007) Management of metastatic cervical cancer: review of the literature. J Clin Oncol 25:2966–2974

    Article  CAS  PubMed  Google Scholar 

  • Lue H, Thiele M, Franz J, Dahl E, Speckgens S, Leng L, Fingerle-Rowson G, Bucala R, Lüscher B, Bernhagen J (2007) Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. Oncogene 26:5046–5059

    Article  CAS  PubMed  Google Scholar 

  • Meyer-Siegler KL, Vera PL, Iczkowski KA, Bifulco C, Lee A, Gregersen PK, Leng L, Bucala R (2007) Macrophage migration inhibitory factor (MIF) gene polymorphisms are associated with increased prostate cancer incidence. Genes Immun 8:646–652

    Article  CAS  PubMed  Google Scholar 

  • Mitchell RA (2004) Mechanisms and effectors of MIF-dependent promotion of tumourigenesis. Cell Signal 16:13–19

    Article  CAS  PubMed  Google Scholar 

  • Muramaki M, Miyake H, Yamada Y, Hara I (2006) Clinical utility of serum macrophage migration inhibitory factor in men with prostate cancer as a novel biomarker of detection and disease progression. Oncol Rep 15:253–257

    PubMed  Google Scholar 

  • Nedergaard BS, Ladekarl M, Nyengaard JR, Nielsen K (2008) A comparative study of the cellular immune response in patients with stage IB cervical squamous cell carcinoma. Low numbers of several immune cell subtypes are strongly associated with relapse of disease within 5 years. Gynecol Oncol 108:106–111

    Article  CAS  PubMed  Google Scholar 

  • Papageorgiou PS, Henley WL, Glade PR (1972) Production and characterization of migration inhibitory factor(s) (MIF) of established lymphoid and non-lymphoid cell lines. J Immunol 108:494–504

    CAS  PubMed  Google Scholar 

  • Petrenko O, Moll UM (2005) Macrophage migration inhibitory factor MIF interferes with the Rb-E2F pathway. Mol Cell 17:225–236

    Article  CAS  PubMed  Google Scholar 

  • Ren Y, Tsui HT, Poon RT, Ng IO, Li Z, Chen Y, Jiang G, Lau C, Yu WC, Bacher M, Fan ST (2003) Macrophage migration inhibitory factor: roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinoma. Int J Cancer 107:22–29

    Article  CAS  PubMed  Google Scholar 

  • Rendon BE, Roger T, Teneng I, Zhao M, Al-Abed Y, Calandra T, Mitchell RA (2007) Regulation of human lung adenocarcinoma cell migration and invasion by macrophage migration inhibitory factor. J Biol Chem 12:282(41):29910–29918

    Google Scholar 

  • Sun B, Nishihira J, Yoshiki T, Kondo M, Sato Y, Sasaki F, Todo S (2005) Macrophage migration inhibitory factor promotes tumor invasion and metastasis via the Rho-dependent pathway. Clin Cancer Res 11:1050–1058

    CAS  PubMed  Google Scholar 

  • Textor S, Dürst M, Jansen L, Accardi R, Tommasino M, Trunk MJ, Porgador A, Watzl C, Gissmann L, Cerwenka A (2008) Activating NK cell receptor ligands are differentially expressed during progression to cervical cancer. Int J Cancer 123:2343–2353

    Article  CAS  PubMed  Google Scholar 

  • Wilson JM, Coletta PL, Cuthbert RJ, Scott N, MacLennan K, Hawcroft G, Leng L, Lubetsky JB, Jin KK, Lolis E, Medina F, Brieva JA, Poulsom R, Markham AF, Bucala R, Hull MA (2005) Macrophage migration inhibitory factor promotes intestinal tumorigenesis. Gastroenterology 129:1485–1503

    Article  CAS  PubMed  Google Scholar 

  • Winner M, Meier J, Zierow S, Rendon BE, Crichlow GV, Riggs R, Bucala R, Leng L, Smith N, Lolis E, Trent JO, Mitchell RA (2008) A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells. Cancer Res 68(18):7253–7257

    Article  CAS  PubMed  Google Scholar 

  • Xu X, Wang B, Ye C, Yao C, Lin Y, Huang X, Zhang Y, Wang S (2008) Overexpression of macrophage migration inhibitory factor induces angiogenesis in human breast cancer. Cancer Lett 261:147–157

    Article  CAS  PubMed  Google Scholar 

  • Yu DS, Hsieh DS, Chang SY (2006a) Increasing expression of GST-pi MIF, and ID1 genes in chemoresistant prostate cancer cells. Arch Androl 52:275–281

    Article  CAS  PubMed  Google Scholar 

  • Yu DS, Lin JC, Hsieh DS, Chang SY, Lee CF (2006b) Modulation of MDR-1 gene by MIF and GSTpi with drug resistance generation in hormone independent prostate cancer. Arch Androl 52:283–291

    Article  CAS  PubMed  Google Scholar 

  • Zhou Q, Yan X, Gershan J, RJ Orentas, BD Johnson (2008) Expression of macrophage migration inhibitory factor by neuroblastoma leads to the inhibition of antitumor T cell reactivity in vivo. J Immunol 181:1877–1886

    CAS  PubMed  Google Scholar 

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Conflict of interest statement

There is no conflict of interest regarding this manuscript.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Wuerzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany

    Mathias Krockenberger, Jörg B. Engel, Julia Kolb, Yvonne Dombrowsky, Sebastian F. M. Häusler, Nico Kohrenhagen, Johannes Dietl, Jörg Wischhusen & Arnd Honig

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  1. Mathias Krockenberger
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  2. Jörg B. Engel
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  3. Julia Kolb
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  4. Yvonne Dombrowsky
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  5. Sebastian F. M. Häusler
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  6. Nico Kohrenhagen
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  7. Johannes Dietl
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  8. Jörg Wischhusen
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  9. Arnd Honig
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Correspondence to Arnd Honig.

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Krockenberger, M., Engel, J.B., Kolb, J. et al. Macrophage migration inhibitory factor expression in cervical cancer. J Cancer Res Clin Oncol 136, 651–657 (2010). https://doi.org/10.1007/s00432-009-0702-5

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  • DOI: https://doi.org/10.1007/s00432-009-0702-5

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