Skip to main content

Advertisement

SpringerLink
Log in

CD147 overexpression is a prognostic factor and a potential therapeutic target in bladder cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

CD147, also named extracellular matrix metalloproteinase inducer (EMMPRIN), has been shown to be involved in the progression of malignancy by regulating expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). The goal of this study was to evaluate the role of CD147 in the biology of bladder cancer and to determine its potential as a therapeutic target. CD147 protein expression was detected by immunohistochemistry in 108 bladder cancers using a tissue microarray annotated with patient follow-up. In immunohistochemistry, CD147 protein expression was associated with poor prognosis (P < 0.001), lymph node status (P < 0.001), tumor stage (P = 0.003), histologic grade (P = 0.011). Multivariate analysis showed that CD147 overexpression was an independent prognostic factor (P = 0.019). Infection of T24 bladder cancer cells with an adenovirus that expressed a small interfering RNA (siRNA) against CD147 efficiently inhibited CD147 protein and mRNA expression. This resulted in decreased proliferation, soft agar colony formation, migration, and invasion of T24 cells in vitro. Moreover, downregulation of CD147 reduced secretion of MMP-2 and MMP-9 and expression of VEGF in these cells. Our findings suggest that CD147 overexpression plays an important role in progression of bladder cancer, and CD147 could be a potential target of bladder cancer therapy.

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

Abbreviations

MMP:

Matrix metalloproteinase

VEGF:

Vascular endothelial growth factor

siRNA:

Small interfering RNA

TCC:

Transitional cell carcinoma

TMA:

Tissue microarray

EMMPRIN(CD147):

Extracellular matrix metalloproteinase inducer

GFP:

Green fluorescent protein

PBS:

Phosphate-buffered saline

HRP:

Horseradish peroxidase

References

  1. Jemal A, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:1–25.

    Article  Google Scholar 

  2. Roth BJ, et al. Significant activity of paclitaxel in advanced transitional cell carcinoma of the urothelium: a PhaseII trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 1994;12:2264–70.

    PubMed  CAS  Google Scholar 

  3. Geller NL, Sternberg CN, Penenberg D, Scher H, Yagoda A. Prognostic factors for survival of patients with advanced urothelial tumors treated with methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy. Cancer. 1991;67:1525–31.

    Article  PubMed  CAS  Google Scholar 

  4. von der Maase H, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23:4602–8.

    Article  Google Scholar 

  5. Biswas C, et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res. 1995;55:434–9.

    PubMed  CAS  Google Scholar 

  6. Muramatsu T, Miyauchi T. Basigin (CD147): a multifunctional transmembrane protein involved in reproduction, neural function, inflammation and tumor invasion. Histol Histopathol. 2003;18:981–7.

    PubMed  CAS  Google Scholar 

  7. Chen X, Kanekura T, Kanski T. Expression of basigin in human fetal, infantile and adult skin and in basal cell carcinoma. J Cutan Pathol. 2001;28:184–90.

    Article  PubMed  CAS  Google Scholar 

  8. Gabison EE, Hoang-Xuan T, Mauviel A, Menasi S. EMMPRIN/CD147, an MMP modulator in cancer, development and tissue repair. Biochimie. 2005;87:361–8.

    Article  PubMed  CAS  Google Scholar 

  9. Zhu P, Ding J, Zhou J, Dong WJ, Fan CM. Expression of CD147 on monocytes/macrophages in rheumatoid arthritis: its potential in monocyte accumulation and metalloproteinase production. Arthritis Res Ther. 2005;7:1023–33.

    Article  Google Scholar 

  10. Nabeshima K, et al. EMMPRIN (basigin/CD147): Matrix metalloproteinase modulator and multifunctional cell recognition molecule that plays a critical role in cancer progression. Pathol Int. 2006;56:359–67.

    Article  PubMed  CAS  Google Scholar 

  11. Yan L, Zucker S, Toole BP. Roles of the multifunctional glycoprotein, emmprin (basigin; CD147), in tumor progression. Thromb Haemost. 2005;93:199–204.

    PubMed  CAS  Google Scholar 

  12. Jin JS, et al. Increasing expression of extracellular matrix metalloproteinase inducer in ovary tumors: tissue microarray analysis of immunostaining score with clinicopathological parameters. Int J Gynecol Pathol. 2006;25:140–6.

    Article  PubMed  Google Scholar 

  13. Sameshima T, et al. Expression of EMMPRIN (CD147), a cell surface inducer of matrix metalloproteinase, in normal human brain and gliomas. Int J Cancer. 2000;88:21–7.

    Article  PubMed  CAS  Google Scholar 

  14. Zheng HC, et al. Upregulated EMMPRIN/CD147 might contribute to growth and angiogenesis of gastric carcinoma: a good marker for local invasion and prognosis. Br J Cancer. 2006;95:1371–8.

    Article  PubMed  CAS  Google Scholar 

  15. Bordador LC, et al. Expression of EMMPRIN by oral squamous cell carcinoma. Int J Cancer. 2000;85:347–52.

    Article  PubMed  CAS  Google Scholar 

  16. Kanekura T, Chen X, Kanznki T. Basigin (CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinase by fibroblast. Int J Cancer. 2002;99:520–8.

    Article  PubMed  CAS  Google Scholar 

  17. Li Y, et al. HAb18G (CD147), a cancer-associated biomarker and its role in cancer detection. Histopathology. 2009;54:677–87.

    Article  PubMed  CAS  Google Scholar 

  18. Zhang Q, et al. Expression of CD147 as a significantly unfavorable prognostic factor in hepatocellular carcinoma. Eur J Cancer Prev. 2007;16:196–202.

    Article  PubMed  Google Scholar 

  19. Tan H, Ye K, Wang Z, Tang H. CD147 expression as a significant prognostic factor in differentiated thyroid carcinoma. Transl Res. 2008;152:143–9.

    Article  PubMed  CAS  Google Scholar 

  20. Reimers N, et al. Expression of extracellular matrix metalloproteinase inducer on micrometastatic and primary mammary carcinoma cells. Clin Cancer Res. 2004;10:3422–8.

    Article  PubMed  CAS  Google Scholar 

  21. Klein CA, et al. Combined transcriptome and genome analysis of single micrometastatic cells. Nat Biotechnol. 2002;20:387–92.

    Article  PubMed  CAS  Google Scholar 

  22. Marieb EA, et al. Emmprin promotes anchorage-independent growth in human mammary carcinoma cells by stimulating hyaluronan production. Cancer Res. 2004;64:1229–32.

    Article  PubMed  CAS  Google Scholar 

  23. Tang Y, et al. Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metalloproteinase. Cancer Res. 2005;65:3193–9.

    PubMed  CAS  Google Scholar 

  24. Muraoka K, et al. Enhanced expression of a tumor-cell-derived collagenase-stimulatory factor in urothelial carcinoma: its usefulness as a tumor marker for bladder cancers. Int J Cancer. 1993;55:19–26.

    Article  PubMed  CAS  Google Scholar 

  25. Als AB, et al. Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer. Clin Cancer Res. 2007;13:4407–14.

    Article  PubMed  CAS  Google Scholar 

  26. Hidalgo A, et al. A simple method for the construction of a small format tissue array. J Clin Pathol. 2003;56:144–6.

    Article  PubMed  CAS  Google Scholar 

  27. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998;22:1435–48.

    CAS  Google Scholar 

  28. Sobin LH, Fleming ID. TNM classification of malignant tumors, 5th edition (1997). Union International Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997;80:1803–4.

    CAS  Google Scholar 

  29. Masters JR, et al. Tissue culture model of transitional cell carcinoma: characterization of twenty-two human urothelial cell lines. Cancer Res. 1986;46:3630–6.

    PubMed  CAS  Google Scholar 

  30. Chen X, et al. A small interfering CD147-targeting RNA inhibited the proliferation, invasiveness, and metastatic activity of malignant melanoma. Cancer Res. 2006;66:11323–30.

    Article  PubMed  CAS  Google Scholar 

  31. Mohan PM, et al. Adenovirus-mediated delivery of antisense gene to urokinase-type plasminogen activator receptor suppresses glioma invasion and tumor growth. Cancer Res. 1999;59:3369–73.

    PubMed  CAS  Google Scholar 

  32. Li Y, et al. Inhibitory effects of antisense RNA of Hab18G/CD147 on invasion of hepatocellular carcinoma cells in vitro. World J Gastroenterol. 2003;9:2174–7.

    PubMed  CAS  Google Scholar 

  33. Yang H, et al. Effects of cyclophilin A on cell proliferation and gene expression in human vascular smooth muscle cells and endothelial cells. J Surg Res. 2005;123:312–9.

    Article  PubMed  CAS  Google Scholar 

  34. Jin ZG, et al. Cyclophilin A is a secreted growth factor induced by oxidative stress. Circ Res. 2000;87:789–96.

    PubMed  CAS  Google Scholar 

  35. Li M, et al. Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147. Cancer. 2006;106:2284–94.

    Article  PubMed  CAS  Google Scholar 

  36. Xu D, Hemler ME. Metabolic activation-related CD147–98 complex. Mol Cell Proteomics. 2005;4:1061–71.

    Article  PubMed  CAS  Google Scholar 

  37. Zucker S, et al. Tumorigenic potential of extracellular matrix metalloproteinase inducer. Am J Pathol. 2001;158:1921–8.

    Article  PubMed  CAS  Google Scholar 

  38. Curran S, Murray GL. Matrix metalloproteinase: molecular aspects of their roles in tumor invasion and metastasis. Eur J Cancer. 2000;36:1621–30.

    Article  PubMed  CAS  Google Scholar 

  39. Dong Z, et al. Matrix metalloproteinase activity and osteoclasts in experimental prostate cancer bone metastasis tissue. Am J Pathol. 2005;166:1173–86.

    Article  PubMed  CAS  Google Scholar 

  40. John A, Tuszynski G. The role of matrix metalloproteinase in tumor angiogenesis and tumor metastasis. Pathol Oncol Res. 2001;7:14–23.

    Article  PubMed  CAS  Google Scholar 

  41. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27.

    Article  PubMed  CAS  Google Scholar 

  42. Nakanishi R, et al. Effect of vascular endothelial growth factor and its receptor inhibitor on proliferation and invasion in bladder cancer. Urol Int. 2009;83:98–106.

    Article  PubMed  CAS  Google Scholar 

  43. Sabine R, et al. High incidence of EMMPRIN expression in human tumors. Int J Cancer. 2006;119:1800–10.

    Article  Google Scholar 

  44. Chen X, et al. Ultrastructural localization of basigin in normal human epidermis. Histochem Cell Biol. 2001;115:465–70.

    PubMed  CAS  Google Scholar 

  45. Kuno N, et al. Female sterility in mice lacking the basigin gene, which encodes a transmembrane glycoprotein belonging to the immunoglobulin superfamily. FEBS Lett. 1998;425:191–4.

    Article  PubMed  CAS  Google Scholar 

  46. Sameshima T, et al. Correlation of EMMPRIN expression in vascular endothelial cells with blood-brain-barrier function: a study using magnetic resonance imaging enhanced by Gd-DTPA and immunohistochemistry in brain tumors. Virchows Arch. 2003;442:577–84.

    PubMed  CAS  Google Scholar 

  47. Coste I, et al. Unavailability of CD147 leads to selective erythrocyte trapping in the spleen. Blood. 2001;97:3984–8.

    Article  PubMed  CAS  Google Scholar 

  48. Gabison EE, et al. Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction. Am J Pathol. 2005;166:209–19.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are very grateful for the sincere help and excellent technical support by the Laboratory of Cell Biology in China Medical University.

Author information

Authors and Affiliations

  1. Department of Urology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, 110001, Shenyang City, Liaoning, China

    Yi-Jun Xue, Qiang Lu & Zhi-Xi Sun

Authors
  1. Yi-Jun Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhi-Xi Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhi-Xi Sun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xue, YJ., Lu, Q. & Sun, ZX. CD147 overexpression is a prognostic factor and a potential therapeutic target in bladder cancer. Med Oncol 28, 1363–1372 (2011). https://doi.org/10.1007/s12032-010-9582-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-010-9582-4

Keywords

Search

Navigation