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Prognostic significance of tissue factor pathway inhibitor-2 in pancreatic carcinoma and its effect on tumor invasion and metastasis

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Abstract

Tissue factor pathway inhibitor-2 (TFPI-2) is a matrix-associated kunitz-type serine proteinase inhibitor that plays an important role in plasmin and trypsin-mediated activation of zymogen matrix metalloproteinases involved in tumor angiogenesis, invasion and metastasis. Earlier studies have shown that the production of TFPI-2 is downregulated during the progression of various tumors. To detect whether TFPI-2 can be expressed in human pancreatic carcinoma samples, to evaluate its prognostic significance on pancreatic carcinoma and to investigate its effect on tumor invasion and metastasis, we collected 9 normal pancreatic tissue samples and 41 pancreatic carcinoma samples and stably transfected the human pancreatic carcinoma cell line Panc-1 with a vector capable of expressing TFPI-2 gene. RT-PCR and Western blot analysis revealed that the expression of TFPI-2 in pancreatic carcinoma samples was markedly lower than that in normal pancreas samples, and there was no TFPI-2 expression in Panc-1 cell. Its expression was related with biological characters of pancreatic carcinoma. The results of Boyden chamber assay and orthotopic pancreatic carcinoma model showed that TFPI-2 could inhibit invasion and metastasis ability of pancreatic carcinoma in vitro and in vivo. Kaplan–Meier survival curve and Cox proportional hazards model assay identified TFPI-2 as an independent prognostic factor for pancreatic carcinoma. Our data suggest that TFPI-2 plays a significant role in the invasion and metastasis of pancreatic carcinoma cell in vitro and in vivo and is determined to be an important prognostic factor for pancreatic carcinoma patients.

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References

  1. Fazal S, Saif MW. Supportive and palliative care of pancreatic cancer. JOP. 2007;8:240–53.

    PubMed  Google Scholar 

  2. Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer. 1995;76:1671–7.

    Article  CAS  PubMed  Google Scholar 

  3. Ellenrieder V, Adler G, Gress TM. Invasion and metastasis in pancreatic cancer. Ann Oncol. 1999;10:46–50.

    Article  PubMed  Google Scholar 

  4. Hirata M, Sato T, Tsumagari M, Hashizume K, Ito A. Discoordinate regulation of expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases-3 in bovine endometrial stromal cells on type-I collagen gel. Biol Pharm Bull. 2003;26:1013–7.

    Article  CAS  PubMed  Google Scholar 

  5. Miyagi Y, et al. Assignment of the human PP5/TFPI-2 gene to 7q22 by FISH and PCR-based human/rodent cell hybrid mapping panel analysis. Genomics. 1996;35:267–8.

    Article  CAS  PubMed  Google Scholar 

  6. Bützow R, Huhtala ML, Bohn H, Virtanen I, Seppälä M. Purification and characterization of placental protein 5. Biochem Biophys Res Commun. 1988;150:483–90.

    Article  PubMed  Google Scholar 

  7. Sprecher CA, Kisiel W, Mathewes S, Foster DC. Molecular cloning, expression, and partial characterization of a second human tissue-factor-pathway inhibitor. Proc Natl Acad Sci USA. 1994;91:3353–7.

    Article  CAS  PubMed  Google Scholar 

  8. Rao CN, et al. Extracellular matrix-associated serine protease inhibitors (M 33, 000, 31, 000 and 27, 000) are single-gene products with differential glycosylation: cDNA cloning of the 33-kDa inhibitor reveals its identity to tissue factor pathway inhibitor-2. Arch Biochem Biophys. 1996;335:82–92.

    Article  CAS  PubMed  Google Scholar 

  9. Rao CN, et al. HT-1080 fibrosarcoma cell matrix degradation and invasion are inhibited by the matrix-associated serine protease inhibitor TFPI-2/33 kDa MSPI. Int J Cancer. 1998;76:749–56.

    Article  CAS  PubMed  Google Scholar 

  10. Izumi H, Takahashi C, Oh J, Noda M. Tissue factor pathway inhibitor-2 suppresses the production of active matrix metalloproteinase-2 and is down-regulated in cells harboring activated ras oncogenes. FEBS Lett. 2000;481:31–6.

    Article  CAS  PubMed  Google Scholar 

  11. Jin M, et al. Expression of serine proteinase inhibitor PP5/TFPI-2/MSPI decreases the invasive potential of human choriocarcinoma cells in vitro and in vivo. Gynecol Oncol. 2001;83:325–33.

    Article  CAS  PubMed  Google Scholar 

  12. Konduri SD, et al. A novel function of tissue factor pathway inhibitor-2 (TFPI-2) in human glioma invasion. Oncogene. 2001;20:6938–45.

    Article  CAS  PubMed  Google Scholar 

  13. Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997;80:1803–4.

    Article  CAS  PubMed  Google Scholar 

  14. Meng Q, et al. Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med. 2001;78:155–65.

    Article  Google Scholar 

  15. Bruns CJ, Harbison MT, Kuniyasu H, Eue I, Fidler IJ. In vivo selection and characterization of metastatic variants from human pancreatic adenocarcinoma by using orthotopic implantation in nude mice. Neoplasia. 1999;1:50–62.

    Article  CAS  PubMed  Google Scholar 

  16. Wojtukiewicz MZ, Sierko E, Zimnoch L, Kozlowski L, Kisiel W. Immunohistochemical localization of tissue factor pathway inhibitor-2 in human tumor tissue. Thromb Haemost. 2003;90:140–6.

    CAS  PubMed  Google Scholar 

  17. Crowe DL, Shuler CF. Regulation of tumor cell invasion by extracellular matrix. Histol Histopathol. 1999;14:665–71.

    CAS  PubMed  Google Scholar 

  18. McCawley LJ, Matrisian LM. Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today. 2000;6:149–56.

    Article  CAS  PubMed  Google Scholar 

  19. Nabeshima K, Inoue T, Shimao Y, Sameshima T. Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol Int. 2002;52:255–64.

    Article  CAS  PubMed  Google Scholar 

  20. Hubé F, Reverdiau P, Iochmann S, Gruel Y. Computer model of the interaction of human TFPI-2 kunitz-type serine protease inhibitor with human plasmin. Thromb Res. 2003;111:197–8.

    Article  PubMed  Google Scholar 

  21. Siegling S, et al. Genetic variation in the human TFPI-2 gene and its promoter region by denaturing high performance liquid chromatography. Thromb Res. 2004;113:341–3.

    Article  CAS  PubMed  Google Scholar 

  22. Chand HS, Schmidt AE, Bajaj SP, Kisiel W. Structure–function analysis of the reactive site in the first kunitz-type domain of human tissue factor pathway inhibitor-2. J Biol Chem. 2004;279:17500–7.

    Article  CAS  PubMed  Google Scholar 

  23. Rao CN, Peavey CL, Liu YY, Lapiere JC, Woodley DT. Partial characterization of matrix-associated serine protease inhibitors from human skin cells. J Invest Dermatol. 1995;104:379–83.

    Article  CAS  PubMed  Google Scholar 

  24. Liu Y, et al. Matrix localization of tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor (TFPI-2/MSPI) involves arginine-mediated ionic interactions with heparin and dermatan sulfate: heparin accelerates the activity of TFPI-2/MSPI toward plasmin. Arch Biochem Biophys. 1999;370:112–8.

    Article  CAS  PubMed  Google Scholar 

  25. Rao CN, Mohanam S, Puppala A, Rao JS. Regulation of ProMMP-1 and ProMMP-3 activation by tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor. Biochem Biophys Res Commun. 1999;255:94–8.

    Article  CAS  PubMed  Google Scholar 

  26. Rollin J, et al. Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer. Br J Cancer. 2005;92:775–83.

    Article  CAS  PubMed  Google Scholar 

  27. Yanamandra N, et al. Recombinant adeno-associated virus (rAAV) expressing TFPI-2 inhibits invasion, angiogenesis and tumor growth in a human glioblastoma cell line. Int J Cancer. 2005;115:998–1005.

    Article  CAS  PubMed  Google Scholar 

  28. Kondraganti S, et al. Restoration of tissue factor pathway inhibitor inhibits invasion and tumor growth in vitro and in vivo in a malignant meningioma cell line. Int J Oncol. 2006;29:25–32.

    CAS  PubMed  Google Scholar 

  29. Konduri SD, Tasiou A, Chandrasekar N, Nicolson GL, Rao JS. Role of tissue factor pathway inhibitor-2 (TFPI-2) in amelanotic melanoma (C-32) invasion. Clin Exp Metastasis. 2000;18:303–8.

    Article  CAS  PubMed  Google Scholar 

  30. Chand HS, et al. The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice. Blood. 2004;103:1069–77.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the Anhui Provincial Natural Science Foundation (No. 0504030702).

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Authors and Affiliations

  1. Department of General Surgery, Affiliated Provincial Hospital, Anhui Medical University, 17 Lujiang Road, 230001, Hefei, Anhui, People’s Republic of China

    Zhigang Tang, Guangyong Geng, Qiang Huang, Geliang Xu, Hejie Hu, Jiong Chen & Jiansheng Li

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  1. Zhigang Tang
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  2. Guangyong Geng
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  3. Qiang Huang
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  4. Geliang Xu
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  5. Hejie Hu
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Correspondence to Zhigang Tang.

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Zhigang Tang and Guangyong Geng contributed equally to this work.

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Tang, Z., Geng, G., Huang, Q. et al. Prognostic significance of tissue factor pathway inhibitor-2 in pancreatic carcinoma and its effect on tumor invasion and metastasis. Med Oncol 27, 867–875 (2010). https://doi.org/10.1007/s12032-009-9298-5

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  • DOI: https://doi.org/10.1007/s12032-009-9298-5

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