Skip to main content

Cyclophilin A promotes human hepatocellular carcinoma cell metastasis via regulation of MMP3 and MMP9

Molecular and Cellular Biochemistry volume 357, pages 387–395 (2011)Cite this article

Abstract

Cyclophilin A (CypA) is a member of peptidyl prolyl isomerases (PPIases), which catalyze the cis/trans isomerization of prolyl peptide bonds on the NH-terminal side of Pro residues in peptide chains. Altered expression of CypA has been reported in hepatocellular carcinoma (HCC), but the biological functions of CypA in HCC remain unknown. We found that the level of CypA expression correlated with the metastatic capability of two HCC cell lines, MHCC97-L and MHCC97-H. Stable expression of ectopic CypA in SK-Hep1 cells promotes cell adhesion, motility, chemotaxis, and in vivo lung metastasis, without affecting cell proliferation. We further analyzed microarray results to identify target genes controlled by CypA. Twenty-one genes related to metastasis were altered by CypA over-expression. A member of matrix metalloproteinase, MMP3, was identified by microarray analysis. The regulation of MMP3 and its homologue MMP9 by CypA were further confirmed by quantitative real-time RT-PCR and zymography assay. Taken together, our data suggest that CypA promotes HCC cell metastasis at least partially through up-regulation of MMP3 and MMP9.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

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

References

  1. Goethel SF, Marahiel MA (1999) Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci 55:423–436

    Article  CAS  Google Scholar 

  2. Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW (1984) Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 226:544–547

    PubMed  Article  CAS  Google Scholar 

  3. Wiederecht G, Lam E, Hung S, Martin M, Sigal N (1993) The mechanism of action of FK-506 and cyclosporin A. Ann NY Acad Sci 696:9–19

    Article  Google Scholar 

  4. Jin ZG, Melaragno MG, Liao DF, Yan C, Haendeler J, Suh YA, Lambeth JD, Berk BC (2000) Cyclophilin A is a secreted growth factor induced by oxidative stress. Circ Res 87:789–796

    PubMed  CAS  Google Scholar 

  5. Sokolskaja E, Luban J (2006) Cyclophilin, TRIM5, and innate immunity to HIV-1. Curr Opin Microbiol 9:404–408

    PubMed  Article  CAS  Google Scholar 

  6. Konttinen YT, Li TF, Mandelin J, Sorsa T, Santavirta S, Virtanen I (2000) Increased expression of extracellular matrix metalloproteinase induce in rheumatoid synovium. Arthritis Rheum 43:275–280

    PubMed  Article  CAS  Google Scholar 

  7. Campa MJ, Wang MZ, Howard B, Fitzgerald MC Jr, Patz EF (2003) Protein expression profiling identifies macrophage migration inhibitory factor and cyclophilin A as potential molecular targets in non-small cell lung cancer. Cancer Res 63:1652–1656

    PubMed  CAS  Google Scholar 

  8. Obama K, Kato T, Hasegawa S, Satoh S, Nakamura Y, Furukawa Y (2006) Overexpression of peptidyl-prolyl isomerase-like 1 is associated with the growth of colon cancer cells. Clin Cancer Res 12:70–76

    PubMed  Article  CAS  Google Scholar 

  9. Chen S, Zhu B, Yu L (2006) In silico comparison of gene expression levels in ten human tumor types reveals candidate genes associated with carcinogenesis. Cytogenet Genome Res 112:53–59

    PubMed  Article  CAS  Google Scholar 

  10. Hussain SA, Ferry DR, El-Gazzaz G, Mirza DF, James ND, McMaster P, Kerr DJ (2001) Hepatocellular carcinoma. Ann Oncol 12:161–172

    PubMed  Article  CAS  Google Scholar 

  11. Tang ZY (2001) Hepatocellular carcinoma—cause, treatment and metastasis. World J Gastroenterol 7:445–454

    PubMed  CAS  Google Scholar 

  12. Poste G, Fidler IJ (1980) The pathogenesis of cancer metastasis. Nature 283:139–146

    PubMed  Article  CAS  Google Scholar 

  13. Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer—trials and tribulations. Science 295:2387–2392

    PubMed  Article  CAS  Google Scholar 

  14. Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, Chen J, Gao DM, Bao WH (2001) Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol 7:630–636

    PubMed  CAS  Google Scholar 

  15. Chen S, Zhang MJ, Ma HH, Saiyin H, Shen SQ, Xi JJ, Wan B, Yu L (2008) Oligo-microarray analysis reveals the role of cyclophilin A in drug resistance. Cancer Chemother Pharmacol 61:459–469

    PubMed  Article  CAS  Google Scholar 

  16. Liu LH, Li CZ, Cai C, Xiang JB, Cao ZG (2010) Cyclophilin A (CypA) is associated with the inflammatory infiltration and alveolar bone destruction in an experimental periodontitis. Biochem Biophys Res Commun 391:1000–1006

    PubMed  Article  CAS  Google Scholar 

  17. Yang Y, Lu N, Zhou J, Chen Z, Zhu P (2008) Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes/macrophages via CD147 signalling pathway in rheumatoid arthritis. Rheumatology 47:1299–1310

    PubMed  Article  CAS  Google Scholar 

  18. Seizera P, Schobergera T, Schota M, Langa MR, Langera HF, Bigalkea B, Kraera BF, Borsta O, Dauba K, Heidenreichb O, Schmidtc R, Lindemanna S, Herouyd Y, Gawaza M, Maya AE (2010) EMMPRIN and its ligand cyclophilin A regulate MT1-MMP, MMP-9 and M-CSF during foam cell formation. Atherosclerosis 209:51–57

    Article  Google Scholar 

  19. Hofmann UB, Houben R, Bröcker EB, Becker JC (2005) Role of matrix metalloproteinases in melanoma cell invasion. Biochimie 87:307–314

    PubMed  Article  CAS  Google Scholar 

  20. Schafer DF, Sorrell MF (1999) Hepatocellular carcinoma. Lancet 353:1253–1257

    PubMed  Article  CAS  Google Scholar 

  21. Liotta LA, Stetler-Stevenson WG, Steeg PS (1991) Cancer invasion and metastasis: positive and negative regulatory elements. Cancer Invest 9:543–551

    PubMed  Article  CAS  Google Scholar 

  22. Lockwood CJ, Oner C, Uz YH, Kayisli UA, Huang SJ, Buchwalder LF, Murk W, Funai EF, Schatz F (2008) Matrix metalloproteinase 9 (MMP9) expression in preeclamptic decidua and MMP9 induction by tumor necrosis factor alpha and interleukin 1 beta in human first trimester decidual cells. Biol Reprod 78:1064–1072

    PubMed  Article  CAS  Google Scholar 

  23. Morris-Wiman J, Burch H, Basco E (2000) Temporospatial distribution of matrix metalloproteinases and tissue inhibitors of metalloproteinases during murine secondary palate morphogenesis. Anat Embryol 202:129–141

    PubMed  Article  CAS  Google Scholar 

  24. Brown NL, Yarram SJ, Mansell JP, Sandy JR (2002) Matrix metalloproteinases have a role in palatogenesis. J Dent Res 81:826–830

    PubMed  Article  CAS  Google Scholar 

  25. Yurchenko V, Zybarth G, O’Connor M, Dai WW, Franchin G, Hao T, Guo H, Hung HC, Toole B, Gallay P, Sherry B, Bukrinsky M (2002) Active site residues of cyclophilin A are crucial for its signaling activity via CD147. J Biol Chem 277:22959–22965

    PubMed  Article  CAS  Google Scholar 

  26. Chen X, Lin J, Takuro K, Su J, Lin W, Xie HF, Wu YX, Li J, Chen ML, Chang J (2006) A small interfering CD147-targeting RNA inhibited the proliferation, invasiveness, and metastatic activity of malignant melanoma. Cancer Res 66:11323–11330

    PubMed  Article  CAS  Google Scholar 

  27. Tomita T, Nakase T, Kaneko M, Shi K, Takahi K, Ochi T, Yoshikawa H (2002) Expression of extracellular matrix metalloproteinase inducer and enhancement of the production of matrix metalloproteinases in rheumatoid arthritis. Arthritis Rheum 46:373–378

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Prof. ZY Tang (Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, P. R. China) for providing MHCC97-L and MHCC97-H cell lines. This work was supported by the National 973 program of China (2004CB518605), the National 863 project of China (2006AA020501), the National Key Sci-Tech Special Project of China (2008ZX10002-020), the Project of the Shanghai Municipal Science and Technology Commission (03dz14086), and the National Natural Science foundation of China (30024001, 30771188).

Author information

Affiliations

  1. State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai, 200433, People’s Republic of China

    Mingjun Zhang, Hengrui Zhu, Shuai Chen, Yanhua Wu, Qiang Li, Xianzhuo Zeng, Wenzhang Wang, Jie Zuo, Mei Zhou, Zongjun Xia, Guoqing Ji, Hexige Saiyin & Long Yu

  2. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, 200433, People’s Republic of China

    Chun Dai & Lunxiu Qin

Authors
  1. Mingjun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chun Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hengrui Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuai Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yanhua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xianzhuo Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wenzhang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jie Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zongjun Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Guoqing Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hexige Saiyin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Lunxiu Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Long Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Long Yu.

Additional information

The first two authors contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 24 kb)

Supplementary material 2 (TIFF 24831 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhang, M., Dai, C., Zhu, H. et al. Cyclophilin A promotes human hepatocellular carcinoma cell metastasis via regulation of MMP3 and MMP9. Mol Cell Biochem 357, 387–395 (2011). https://doi.org/10.1007/s11010-011-0909-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-0909-z

Keywords

  • Cyclophilin A (CypA)
  • Hepatocellular carcinoma (HCC)
  • Metastasis
  • Microarray
  • Matrix metalloproteinase (MMP)