Histochemistry and Cell Biology

, Volume 132, Issue 6, pp 639–646 | Cite as

Prostasin inhibits cell invasion in human choriocarcinomal JEG-3 cells

  • Xiao-jie Ma
  • Ya-yuan Fu
  • Yu-xia Li
  • Li-mei Chen
  • Karl Chai
  • Yan-ling Wang
Original Paper


Controlled invasion of the uterine wall by the trophoblast cells is pivotal for the successful pregnancy, and various kinds of protease are involved in this process. Serine protease prostasin has been shown to participate in the proteolytic activation of epithelial sodium channel as well as cleavage of epidermal growth factor receptor extracellular domain in human epithelial cells. Its physiological significance in human placentation has been suggested but not validated. In the present study, we found that prostasin was expressed at a relatively high level in human placenta trophoblasts in early pregnant weeks. In the in vitro cultured human choriocarcinomal JEG-3 cells, treatment with functional antibody against prostasin led to promotion in cell invasion capability, as well as increase in the production of MMP-2, MMP-26, TIMP-1, and TIMP-4. Our data indicated that this serine protease may function as an invasion suppressor in human trophoblast, participating in the invasion-restrictive regulation of trophoblasts to avoid their over-penetration into the uterine wall.


Prostasin Cell invasion Choriocarcinomal JEG-3 cell MMPs/TIMPs Integrins 



The work was supported by the grants from National Natural Sciences Foundation (No. 30530760), the Chinese National Special Fund for Basic Research Project (No. 2006CB944008) and the Knowledge Innovation Program in Chinese Academy of Sciences (No. KSCX2-YW-R-53). The authors appreciate the kind gift of MMP-26 and TIMP-4 antibodies from Dr. Qing-xiang Amy Sang at Florida State University).


  1. Adachi M, Kitamura K, Miyoshi T, Narikiyo T, Iwashita K, Shiraishi N, Nonoguchi H, Tomita K (2001) Activation of epithelial sodium channels by prostasin in Xenopus oocytes. J Am Soc Nephrol 12:1114–1121PubMedGoogle Scholar
  2. Bruns JB, Carattino MD, Sheng S, Maarouf AB, Weisz OA, Pilewski JM, Hughey RP, Kleyman TR (2007) Epithelial Na+ channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the gamma-subunit. J Biol Chem 282:6153–6160CrossRefPubMedGoogle Scholar
  3. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity. Cancer Res 47:943–946 Google Scholar
  4. Chen LM, Hodge GB, Guarda LA, Welch JL, Greenberg NM, Chai KX (2001a) Down-regulation of prostasin serine protease: a potential invasion suppressor in prostate cancer. Prostate 48:93–103CrossRefPubMedGoogle Scholar
  5. Chen LM, Skinner ML, Kauffman SW, Chao J, Chao L, Thaler CD, Chai KX (2001b) Prostasin is a glycosylphosphatidylinositol-anchored active serine protease. J Biol Chem 276:21434–21442CrossRefPubMedGoogle Scholar
  6. Chen LM, Zhang X, Chai KX (2004) Regulation of prostasin expression and function in the prostate. Prostate 59:1–12CrossRefPubMedGoogle Scholar
  7. Chen M, Fu YY, Lin CY, Chen LM, Chai KX (2007) Prostasin induces protease-dependent and independent molecular changes in the human prostate carcinoma cell line PC-3. Biochim Biophys Acta 1773:1133–1140CrossRefPubMedGoogle Scholar
  8. Chen M, Chen LM, Lin CY, Chai KX (2008) The epidermal growth factor receptor (EGFR) is proteolytically modified by the Matriptase-Prostasin serine protease cascade in cultured epithelial cells. Biochim Biophys Acta 1783:896–903CrossRefPubMedGoogle Scholar
  9. Cohen M, Bischof P (2007) Factors regulating trophoblast invasion. Gynecol Obstet Invest 64:126–130CrossRefPubMedGoogle Scholar
  10. Damsky CH, Werb Z (1992) Signal transduction by integrin receptors for extracellular matrix: cooperative processing of extracellular information. Curr Opin Cell Biol 4:772–781CrossRefPubMedGoogle Scholar
  11. Damsky CH, Fitzgerald ML, Fisher SJ (1992) Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo. J Clin Invest 89:210–222CrossRefPubMedGoogle Scholar
  12. Damsky CH, Librach C, Lim KH, Fitzgerald ML, McMaster MT, Janatpour M, Zhou Y, Logan SK, Fisher SJ (1994) Integrin switching regulates normal trophoblast invasion. Development 120:3657–3666PubMedGoogle Scholar
  13. Diakov A, Bera K, Mokrushina M, Krueger B, Korbmacher C (2008) Cleavage in the {gamma}-subunit of the epithelial sodium channel (ENaC) plays an important role in the proteolytic activation of near-silent channels. J Physiol 586:4587–4608CrossRefPubMedGoogle Scholar
  14. Fan B, Wu TD, Li W, Kirchhofer D (2005) Identification of hepatocyte growth factor activator inhibitor-1B as a potential physiological inhibitor of prostasin. J Biol Chem 280:34513–34520CrossRefPubMedGoogle Scholar
  15. Goldman-Wohl D, Yagel S (2002) Regulation of trophoblast invasion: from normal implantation to pre-eclampsia. Mol Cell Endocrinol 187:233–238CrossRefPubMedGoogle Scholar
  16. Guzeloglu-Kayisli O, Basar M, Arici A (2007) Basic aspects of implantation. Reprod Biomed Online 15:728–739PubMedCrossRefGoogle Scholar
  17. Knofler M, Sooranna SR, Daoud G, Whitley GS, Markert UR, Xia Y, Cantiello H, Hauguel-de Mouzon S (2005) Trophoblast signalling: knowns and unknowns—a workshop report. Placenta 26(Suppl A):S49–S51CrossRefPubMedGoogle Scholar
  18. Lin HY, Zhang H, Yang Q, Wang HX, Wang HM, Chai KX, Chen LM, Zhu C (2006) Expression of prostasin and protease nexin-1 in rhesus monkey (Macaca mulatta) endometrium and placenta during early pregnancy. J Histochem Cytochem 54:1139–1147CrossRefPubMedGoogle Scholar
  19. Maekawa A, Kakizoe Y, Miyoshi T, Wakida N, Ko T, Shiraishi N, Adachi M, Tomita K, Kitamura K (2009) Camostat mesilate inhibits prostasin activity and reduces blood pressure and renal injury in salt-sensitive hypertension. J Hypertens 27:181–189CrossRefPubMedGoogle Scholar
  20. Murray MJ, Lessey BA (1999) Embryo implantation and tumor metastasis: common pathways of invasion and angiogenesis. Semin Reprod Endocrinol 17:275–290CrossRefPubMedGoogle Scholar
  21. Narikiyo T, Kitamura K, Adachi M, Miyoshi T, Iwashita K, Shiraishi N, Nonoguchi H, Chen LM, Chai KX, Chao J, Tomita K (2002) Regulation of prostasin by aldosterone in the kidney. J Clin Invest 109:401–408PubMedGoogle Scholar
  22. Netzel-Arnett S, Currie BM, Szabo R, Lin CY, Chen LM, Chai KX, Antalis TM, Bugge TH, List K (2006) Evidence for a matriptase-prostasin proteolytic cascade regulating terminal epidermal differentiation. J Biol Chem 281:32941–32945CrossRefPubMedGoogle Scholar
  23. Olivieri O, Castagna A, Guarini P, Chiecchi L, Sabaini G, Pizzolo F, Corrocher R, Righetti PG (2005) Urinary prostasin: a candidate marker of epithelial sodium channel activation in humans. Hypertension 46:683–688CrossRefPubMedGoogle Scholar
  24. Pilka R, Kudela M, Prochazka M (2003) Matrix metalloproteinases, embryo implantation and tumor invasion. Ceska Gynekol 68:179–185PubMedGoogle Scholar
  25. Qin L, Wang YL, Bai SX, Ji SH, Qiu W, Tang S, Piao YS (2003) Temporal and spatial expression of integrins and their extracellular matrix ligands at the maternal-fetal interface in the rhesus monkey during pregnancy. Biol Reprod 69:563–571CrossRefPubMedGoogle Scholar
  26. Qiu Q, Yang M, Tsang BK, Gruslin A (2004) EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways. Reproduction 128:355–363CrossRefPubMedGoogle Scholar
  27. Qiu W, Bai SX, Zhao MR, Wu XQ, Zhao YG, Sang QX, Wang YL (2005) Spatio-temporal expression of matrix metalloproteinase-26 in human placental trophoblasts and fetal red cells during normal placentation. Biol Reprod 72:954–959CrossRefPubMedGoogle Scholar
  28. Rotin D, Schild L (2008) ENaC and its regulatory proteins as drug targets for blood pressure control. Curr Drug Targets 9:709–716CrossRefPubMedGoogle Scholar
  29. Salamonsen LA (1999) Role of proteases in implantation. Rev Reprod 4:11–22CrossRefPubMedGoogle Scholar
  30. Soundararajan R, Rao AJ (2004) Trophoblast ‘pseudo-tumorigenesis’: significance and contributory factors. Reprod Biol Endocrinol 2:15CrossRefPubMedGoogle Scholar
  31. Staun-Ram E, Goldman S, Gabarin D, Shalev E (2004) Expression and importance of matrix metalloproteinase 2 and 9 (MMP-2 and -9) in human trophoblast invasion. Reprod Biol Endocrinol 2:59CrossRefPubMedGoogle Scholar
  32. Takahashi S, Suzuki S, Inaguma S, Ikeda Y, Cho YM, Hayashi N, Inoue T, Sugimura Y, Nishiyama N, Fujita T, Chao J, Ushijima T, Shirai T (2003) Down-regulated expression of prostasin in high-grade or hormone-refractory human prostate cancers. Prostate 54:187–193CrossRefPubMedGoogle Scholar
  33. Wang C, Chao J, Chao L (2003) Adenovirus-mediated human prostasin gene delivery is linked to increased aldosterone production and hypertension in rats. Am J Physiol Regul Integr Comp Physiol 284:R1031–R1036PubMedGoogle Scholar
  34. Xu P, Wang YL, Zhu SJ, Luo SY, Piao YS, Zhuang LZ (2000) Expression of matrix metalloproteinase-2, -9, and -14, tissue inhibitors of metalloproteinase-1, and matrix proteins in human placenta during the first trimester. Biol Reprod 62:988–994CrossRefPubMedGoogle Scholar
  35. Yu JX, Chao L, Chao J (1994) Prostasin is a novel human serine proteinase from seminal fluid. Purification, tissue distribution, and localization in prostate gland. J Biol Chem 269:18843–18848PubMedGoogle Scholar
  36. Yu JX, Chao L, Chao J (1995) Molecular cloning, tissue-specific expression, and cellular localization of human prostasin mRNA. J Biol Chem 270:13483–13489PubMedGoogle Scholar
  37. Zhang J, Cao YJ, Zhao YG, Sang QX, Duan EK (2002) Expression of matrix metalloproteinase-26 and tissue inhibitor of metalloproteinase-4 in human normal cytotrophoblast cells and a choriocarcinoma cell line, JEG-3. Mol Hum Reprod 8:659–666CrossRefPubMedGoogle Scholar
  38. Zhu H, Chao J, Guo D, Li K, Huang Y, Hawkins K, Wright N, Stallmann-Jorgenson I, Yan W, Harshfield GA, Dong Y (2008) Urinary prostasin: a possible biomarker for renal pressure natriuresis in black adolescents. Pediatr Res 65(4):443–446CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Xiao-jie Ma
    • 1
    • 3
  • Ya-yuan Fu
    • 1
    • 3
  • Yu-xia Li
    • 1
  • Li-mei Chen
    • 2
  • Karl Chai
    • 2
  • Yan-ling Wang
    • 1
  1. 1.State Key Laboratory of Reproductive Biology, Institute of ZoologyChinese Academy of SciencesBeijingChina
  2. 2.Department of Molecular Biology and MicrobiologyUniversity of Central FloridaOrlandoUSA
  3. 3.Graduate School of Chinese Academy of SciencesBeijingChina

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