Skip to main content
Log in

Macrophage immigration inhibitory factor promotes cell proliferation and inhibits apoptosis of cervical adenocarcinoma

  • Research Article
  • Published:
Tumor Biology

Abstract

As a multifunctional cytokine, macrophage migration inhibitory factor (MIF) is associated with inflammation and tumorigenesis; however, the role of MIF in cervical adenocarcinoma (ADC) is not fully understood. In this study, we aimed to examine the expression of MIF in ADC and explore the mechanism of MIF in ADC progression. MIF expression was positively related to ADC clinicopathological features of carcinoma diameter and lymph node metastasis. MIF knockdown induced cell cycle arrest of G1/S transition in ADC cells, upregulation of the expressions of p21 and p27, and downregulation of the expressions of Cdk4, CyclinD2, and CyclinE2. In MIF knockdown cells, the expressions of proapoptotic proteins of Bax, caspase-3, cleaved caspase-3, and cleaved-PARP were upregulated, and the expressions of antiapoptotic proteins of Bcl-2, pAkt, and p53 were downregulated. It indicated that MIF knockdown inhibited cell proliferation and induced apoptosis in ADC cells. MIF might be a novel molecular marker in diagnosis and therapy of ADC.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Seoud M, Tjalma WA, Ronsse V. Cervical adenocarcinoma: moving towards better prevention. Vaccine. 2011;29:9148–58.

    Article  PubMed  Google Scholar 

  3. Mathew A, George PS. Trends in incidence and mortality rates of squamous cell carcinoma and adenocarcinoma of cervix-worldwide. Asian Pac J Cancer Prev. 2009;10:645–50.

    PubMed  Google Scholar 

  4. Galic V, Herzog TJ, Lewin SN, Neugut AI, Burke WM, Lu YS, et al. Prognostic significance of adenocarcinoma histology in women with cervical cancer. Gynecol Oncol. 2012;5:36–41.

    Google Scholar 

  5. McLaughlin-Drubin ME, Meyers J, Munger K. Cancer associated human papil-lomaviruses. Curr Opin Virol. 2012;2:459–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Grabowska AK, Riemer AB. The invisible enemy—how human papillomaviruses avoid recognition and clearance by the host immune system. OpenVirol J. 2012;6:249–56.

    Google Scholar 

  7. Plummer M, Schiffman M, Castle PE, Maucort-Boulch D, Wheeler CM, ALTS. Group. A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis. 2007;195:1582–9.

    Article  PubMed  Google Scholar 

  8. de Freitas AC, Coimbra EC, Leitão Mda C. Molecular targets of HPV oncoproteins: potential biomarkers for cervical carcinogenesis. Biochim Biophys Acta. 2014;1845:91–103.

    PubMed  Google Scholar 

  9. Grieb G, Merk M, Bernhagen J, Bucala R. Macrophage migration inhibitory factor (MIF): a promising biomarker. Drug News Perspect. 2010;23:257–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Santos LL, Morand EF. Macrophage migration inhibitory factor: a key cytokine in RA. SLE and atherosclerosis. Clin Chim Acta. 2009;399:1–7.

    Article  CAS  PubMed  Google Scholar 

  11. Conroy H, Mawhinney L, Donnelly SC. Inflammation and cancer: macrophage migration inhibitory factor (MIF) - the potential missing link. QJM. 2010;103:831–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mitchell RA. Mechanisms and effectors of MIF-dependent promotion of tumourigenesis. Cell Signal. 2004;16:13–9.

    Article  CAS  PubMed  Google Scholar 

  13. Brock SE, Rendon BE, Xin D, Yaddanapudi K, Mitchell RA. MIF family members cooperatively inhibit p53 expression and activity. PLoS. 2014;9:e99795.

    Article  Google Scholar 

  14. Richard V, Kindt N, Decaestecker C, Gabius HJ, Laurent G, Noël JC, et al. Involvement of macrophage migration inhibitory factor and its receptor (CD74) in human breast cancer. Oncol Rep. 2014;32:523–9.

    PubMed  PubMed Central  Google Scholar 

  15. Cheng RJ, Deng WG, Niu CB, Li YY, Fu Y. Expression of macrophage migration inhibitory factor and CD74 in cervical squamous cell carcinoma. Int J Gynecol Cancer. 2011;21:1004–12.

    Article  PubMed  Google Scholar 

  16. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–12.

    Article  CAS  PubMed  Google Scholar 

  17. Gudas JM, Payton M, Thukral S, Chen E, Bass M, Robinson MO, et al. Cyclin E2, a novel G1 cyclin that binds Cdk2 and is aberrantly expressed in human cancers. Mol Cell Biol. 1999;19:612–22.

    Article  CAS  PubMed  Google Scholar 

  18. Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, et al. The p21 (Cip1) and p27 (Kip1) CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J. 1999;18:1571–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yoshino T, Shiina H, Urakami S, Kikuno N, Yoneda T, Shigeno K, et al. Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy. Clin Cancer Res. 2006;33:6116–24.

    Article  Google Scholar 

  20. MacCarthy-Morrogh L, Mouzakiti A, Townsend P, Brimmell M, Packham G. Bcl-2-related proteins and cancer. Biochem Soc Trans. 1999;27:785–9.

    Article  CAS  PubMed  Google Scholar 

  21. Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol. 1993;4:327–32.

    CAS  PubMed  Google Scholar 

  22. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hassa PO, Hottiger MO. The diverse biological roles of mammalian PARPs, a small but powerful family of poly-ADP-ribose polymerases. Front Biosci. 2008;13:3046–82.

    Article  CAS  PubMed  Google Scholar 

  24. Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly (ADP ribose) and PARPs. Nat Rev Mol Cell Biol. 2012;13:411–24.

    Article  CAS  PubMed  Google Scholar 

  25. Qi Z, Liu M, Liu Y, Zhang M, Yang G. Tetramethpxychalcone, a chalcone derivative, suppress proliferation, blocks cell cycle progression and induces apoptosis of human ovarion cancer cells. PLoS One. 2014;9:e105206.

    Article  Google Scholar 

  26. Winter RN, Kramer A, Borkowski A, Kyprianou N. Loss of caspase-1 and caspase-3 protein expression in human prostate cancer. Cancer Res. 2001;61:1227–32.

    CAS  PubMed  Google Scholar 

  27. Chauhan D, Pandey P, Ogata A, Teoh G, Krett N, Halgren R, et al. Cytochrome c-dependent and independent induction of apoptosis in multiple myeloma cells. J Biol Chem. 1997;272:29995–7.

    Article  CAS  PubMed  Google Scholar 

  28. Baumann R, Casaulta C, Simon D, Conus S, Yousefi S, Simon HU. Macrophage migration inhibitory factor delays apoptosis in neutrophils by inhibiting the mitochondria-dependent death pathway. FASEB J. 2003;17:2221–30.

    Article  CAS  PubMed  Google Scholar 

  29. Downward J. How BAD, phosphorylation is good for survival. Nat Cell Biol. 1999;1:E33–5.

    Article  CAS  PubMed  Google Scholar 

  30. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 1995;80:285–91.

    Article  CAS  PubMed  Google Scholar 

  31. Fernando R, Foster JS, Bible A, Strom A, Pestell RG, Rao M, et al. Breast cancer cell proliferation is inhibited by BAD: regulation of cyclin D1. J Biol Chem. 2007;282:28864–73.

    Article  CAS  PubMed  Google Scholar 

  32. Li J, Man L, Dan L, Bojiang C, Wen Z, Lin M, et al. BAD overexpression inhibits cell growth and induces apoptosis via mitochondrial-dependent pathway in non-small cell lung cancer. Cancer Cell Int. 2013;13:53.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lue H, Thiele M, Franz J, Dahl E, Speckgens S, Leng L, et al. 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. 2007;26:5046–59.

    Article  CAS  PubMed  Google Scholar 

  34. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26:1932–40.

    Article  CAS  PubMed  Google Scholar 

  35. Kandel ES, Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res. 1999;253:210–29.

    Article  CAS  PubMed  Google Scholar 

  36. Blanco-Aparicio C, Renner O, Leal JF, Carnero A. PTEN, more than the AKT pathway. Carcinogenesis. 2007;28:1379–86.

    Article  CAS  PubMed  Google Scholar 

  37. Huang XH, Jian WH, Wu ZF, Zhao J, Wang H, Li W, et al. Small interfering RNA (siRNA)-mediated knockdown of macrophage migration inhibitory factor (MIF) suppressed cyclin D1 expression and hepatocellular carcinoma cell proliferation. Oncotarget. 2014;5:5570–80.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Mitsiades CS, Mitsiades N, Poulaki V, Schlossman R, Akiyama M, Chauhan D, et al. Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene. 2002;21:5673–83.

    Article  CAS  PubMed  Google Scholar 

  39. Fingerle-Rowson G, Petrenko O, Metz CN, Forsthuber TG, Mitchell R, Mitchell R, et al. The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc Natl Acad Sci U S A. 2003;100:9354–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mitchell RA, Liao H, Chesney J, Fingerle-Rowson G, Baugh J, David J, et al. Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proc Natl Acad Sci U S A. 2002;99:345–50.

    Article  CAS  PubMed  Google Scholar 

  41. Gore Y, Starlets D, Maharshak N, Becker-Herman S, Kaneyuki U, Leng L, et al. Macrophage migration inhibitory factor induces B cell survival by activation of a CD74-CD44 receptor complex. J Biol Chem. 2008;283:2784–92.

    Article  CAS  PubMed  Google Scholar 

  42. Schwartz V, Lue H, Kraemer S, Korbiel J, Krohn R, Ohl K, et al. A functional heteromeric MIF receptor formed by CD74 and CXCR4. FEBS Lett. 2009;583:2749–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 2007;13:587–96.

    Article  CAS  PubMed  Google Scholar 

  44. Chatterjee M, Borst O, Walker B, Fotinos A, Vogel S, Seizer P, et al. Macrophage migration inhibitory factor limits activation-induced apoptosis of platelets via CXCR7-dependent Akt signaling. Circ Res. 2014;115:939–49.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The National Natural Science Foundation of China (No. 81172337, 30973395); Natural Science Foundation of Guangdong Province of China (S2011010003516, S2011010004793)

Conflicts of interest

None

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Wen Li or Mian He.

Additional information

Peng Guo and Jing Wang have an equal contribution to this study work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, P., Wang, J., Liu, J. et al. Macrophage immigration inhibitory factor promotes cell proliferation and inhibits apoptosis of cervical adenocarcinoma. Tumor Biol. 36, 5095–5102 (2015). https://doi.org/10.1007/s13277-015-3161-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3161-4

Keywords

Navigation