Skip to main content
SpringerLink
Log in

Overexpression of macrophage migration inhibitory factor in adenoid cystic carcinoma: correlation with enhanced metastatic potential

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Objectives

Adenoid cystic carcinoma (ACC) is a malignant tumor frequently arising in salivary glands with poor long-term prognosis due to high rates of local recurrences and distant metastases. Macrophage migration inhibitory factor (MIF) is a multi-functional cytokine and has recently emerged as a pro-tumorigenic factor in various cancers. This study is designed to investigate the expression status and functional significance of MIF in ACC.

Methods

Immunohistochemical staining was performed to evaluate the expression levels of MIF, HIF-1α, MMP-9, p53, and p-JNK in ACC tissues. In vitro, ACC-2 cells were exposed to recombinant human MIF (rMIF) or ISO-1 (an inhibitor of MIF) at different concentrations and times, followed by the detection of cell growth, viability, migration, and invasion, as well as the expression levels of several cellular signals.

Results

The immunohistochemical results demonstrated the overexpression of MIF in ACC tissues as well as its association with the distant metastasis. Further analyses showed a significant correlation between the staining of MIF and p-JNK. Moreover, the in vitro studies revealed that the treatment for ACC cells with ISO-1 significantly attenuated cell migratory and invasive capacity, as opposed to the limited promotive effects of rMIF. More importantly, MIF inhibition could cause the activation of JNK, correlating with the immunohistochemical findings on ACC tissues.

Conclusions

The results suggest that MIF is likely to be an important player in the pathogenesis of ACC and may promote cancer metastasis, which possibly involves JNK inactivation. Further investigation of MIF-mediated molecular events may provide novel insights into the treatment for ACC.

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

Similar content being viewed by others

References

  • Al-Abed Y, VanPatten S (2011) MIF as a disease target: ISO-I as a proof-of-concept therapeutic. Futur Med Chem 3(1):45–63

    Article  CAS  Google Scholar 

  • Bach JP, Deuster O et al (2009) The role of macrophage inhibitory factor in tumorigenesis and central nervous system tumors. Cancer 115(10):2031–2040

    Article  PubMed  CAS  Google Scholar 

  • Balachandran S, Rodge A et al (2009) Novel derivatives of ISO-1 as potent inhibitors of MIF biological function. Bioorg Med Chem Lett 19(16):4773–4776

    Article  PubMed  CAS  Google Scholar 

  • Bifulco C, McDaniel K et al (2008) Tumor growth-promoting properties of macrophage migration inhibitory factor. Curr Pharm Des 14(36):3790–3801

    Article  PubMed  CAS  Google Scholar 

  • Bucala R, Donnelly SC (2007) Macrophage migration inhibitory factor: a probable link between inflammation and cancer. Immunity 26(3):281–285

    Article  PubMed  CAS  Google Scholar 

  • Chen G, Hu X et al (2012) Mammalian target of rapamycin regulates isoliquiritigenin-induced autophagic and apoptotic cell death in adenoid cystic carcinoma cells. Apoptosis 17(1):90–101

    Article  PubMed  CAS  Google Scholar 

  • Dodd RL, Slevin NJ (2006) Salivary gland adenoid cystic carcinoma: a review of chemotherapy and molecular therapies. Oral Oncol 42(8):759–769

    Article  PubMed  CAS  Google Scholar 

  • Dumitru CA, Gholaman H et al (2011) Tumor-derived macrophage migration inhibitory factor modulates the biology of head and neck cancer cells via neutrophil activation. Int J Cancer 129(4):859–869

    Article  PubMed  CAS  Google Scholar 

  • Fridman R, Toth M et al (2003) Cell surface association of matrix metalloproteinase-9 (gelatinase B). Cancer Metastasis Rev 22(2–3):153–166

    Article  PubMed  CAS  Google Scholar 

  • Heeren PA, Kloppenberg FW et al (2004) Predictive effect of p53 and p21 alteration on chemotherapy response and survival in locally advanced adenocarcinoma of the esophagus. Anticancer Res 24(4):2579–2583

    PubMed  Google Scholar 

  • Huang C, Sun Z et al (2012) Association of increased ligand cyclophilin A and receptor CD147 with hypoxia, angiogenesis, metastasis and prognosis of tongue squamous cell carcinoma. Histopathology 60(5):793–803

    Article  PubMed  Google Scholar 

  • Jung H, Seong HA et al (2008) Critical role of cysteine residue 81 of macrophage migration inhibitory factor (MIF) in MIF-induced inhibition of p53 activity. J Biol Chem 283(29):20383–20396

    Article  PubMed  CAS  Google Scholar 

  • Kleemann R, Hausser A et al (2000) Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408(6809):211–216

    Article  PubMed  CAS  Google Scholar 

  • Krockenberger M, Engel JB et al (2010) Macrophage migration inhibitory factor expression in cervical cancer. J Cancer Res Clin Oncol 136(5):651–657

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Shao C et al (2011) Molecular biology of adenoid cystic carcinoma. Head Neck. doi:10.1002/hed.21849

  • Lue H, Dewor M et al (2011) Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74. Cell Signal 23(1):135–144

    Article  PubMed  CAS  Google Scholar 

  • Meyer-Siegler KL, Iczkowski KA et al (2006) Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells. J Immunol 177(12):8730–8739

    PubMed  CAS  Google Scholar 

  • Nabizadeh Marvast M, Sima HR et al (2011) Clinicopathological significance of macrophage migration inhibitory factor and its relation with p53 in gastric cancer. J Gastrointest Cancer 42(1):5–10

    Article  PubMed  Google Scholar 

  • Oda S, Oda T et al (2008) Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner. PLoS ONE 3(5):e2215

    Article  PubMed  Google Scholar 

  • Piao S, Zhao S et al (2012) Increased expression of CD147 and MMP-9 is correlated with poor prognosis of salivary duct carcinoma. J Cancer Res Clin Oncol 138(4):627–635

    Article  PubMed  CAS  Google Scholar 

  • Qi D, Hu X et al (2009) Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion. J Clin Invest 119(12):3807–3816

    Article  PubMed  CAS  Google Scholar 

  • Rendon BE, Roger T et al (2007) Regulation of human lung adenocarcinoma cell migration and invasion by macrophage migration inhibitory factor. J Biol Chem 282(41):29910–29918

    Article  PubMed  CAS  Google Scholar 

  • Rendon BE, Willer SS et al (2009) Mechanisms of macrophage migration inhibitory factor (MIF)-dependent tumor microenvironmental adaptation. Exp Mol Pathol 86(3):180–185

    Article  PubMed  CAS  Google Scholar 

  • Salminen A, Kaarniranta K (2011) Control of p53 and NF-kappaB signaling by WIP1 and MIF: role in cellular senescence and organismal aging. Cell Signal 23(5):747–752

    Article  PubMed  CAS  Google Scholar 

  • Spiro RH (1997) Distant metastasis in adenoid cystic carcinoma of salivary origin. Am J Surg 174(5):495–498

    Article  PubMed  CAS  Google Scholar 

  • Sun ZJ, Chen G et al (2010a) Activation of PI3 K/Akt/IKK-alpha/NF-kappaB signaling pathway is required for the apoptosis-evasion in human salivary adenoid cystic carcinoma: its inhibition by quercetin. Apoptosis 15(7):850–863

    Article  PubMed  CAS  Google Scholar 

  • Sun ZJ, Chen G et al (2010b) Mammalian target of rapamycin pathway promotes tumor-induced angiogenesis in adenoid cystic carcinoma: its suppression by isoliquiritigenin through dual activation of c-Jun NH2-terminal kinase and inhibition of extracellular signal-regulated kinase. J Pharmacol Exp Ther 334(2):500–512

    Article  PubMed  CAS  Google Scholar 

  • Sun ZJ, Chen G et al (2011) Curcumin dually inhibits both mammalian target of rapamycin and nuclear factor-kappaB pathways through a crossed phosphatidylinositol 3-kinase/Akt/IkappaB kinase complex signaling axis in adenoid cystic carcinoma. Mol Pharmacol 79(1):106–118

    Article  PubMed  CAS  Google Scholar 

  • Suzuki F, Nakamaru Y et al (2005) Prognostic significance of cytoplasmic macrophage migration inhibitory factor expression in patients with squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy. Oncol Rep 13(1):59–64

    PubMed  Google Scholar 

  • Tang Y, Liang X et al (2010) Expression of c-kit and Slug correlates with invasion and metastasis of salivary adenoid cystic carcinoma. Oral Oncol 46(4):311–316

    Article  PubMed  CAS  Google Scholar 

  • Wagner EF, Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9(8):537–549

    Article  PubMed  CAS  Google Scholar 

  • Winner M, Koong AC et al (2007) Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization. Cancer Res 67(1):186–193

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work is supported by the grants from National Natural Science Foundation of China (81072203) to Dr. Z. J. Sun, and (30973330) to Prof. Y. F. Zhao.

Conflict of interest

No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

  1. The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China

    Hui Liu, Gang Chen, Wei Zhang, Jun-Yi Zhu, Feng-Qin Wang, Jun Jia, Zhi-Jun Sun & Yi-Fang Zhao

  2. Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China

    Gang Chen, Jun Jia, Zhi-Jun Sun & Yi-Fang Zhao

  3. Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, China

    Hui Liu, Zhao-Quan Lin & Zhong-Cheng Gong

Authors
  1. Hui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun-Yi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhao-Quan Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhong-Cheng Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Feng-Qin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jun Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhi-Jun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yi-Fang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jun Jia or Yi-Fang Zhao.

Additional information

Hui Liu and Gang Chen contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 496 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, H., Chen, G., Zhang, W. et al. Overexpression of macrophage migration inhibitory factor in adenoid cystic carcinoma: correlation with enhanced metastatic potential. J Cancer Res Clin Oncol 139, 287–295 (2013). https://doi.org/10.1007/s00432-012-1330-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-012-1330-z

Keywords

Search

Navigation