Skip to main content
SpringerLink
Log in

β-catenin signaling involves HGF-enhanced HepG2 scattering through activating MMP-7 transcription

  • Original Article
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

It is well accepted that cell scattering (dispersion of clustered cells into single cells) is the initial step of tumor metastasis, and the downregulation of E-cadherin is associated with metastatic potential of tumor cells; however, the molecular mechanisms underlying loss of E-cadherin during tumor development are still poorly understood. Here, we report that hepatocyte growth factor (HGF) induced E-cadherin downregulation and cell scattering are attributed to the activation of Wnt/β-catenin signaling and transcriptional activation of matrix metalloproteinase MMP-7. Furthermore, the increased MMP-7 is secreted into the medium and cleaves the ectodomain of E-cadherin. Inhibition of HGF signal by siRNA of c-Met, blocking the β-catenin transcriptional activity through a dominant negative form of TCF4, MMP-7 knockdown by siRNA or suppression of MMP-7 enzymatic activity with a neutralization antibody allowed inhibition of HGF-induced loss of E-cadherin and HepG2 scattering. Our data presented here revealed the intrinsic mechanism of HGF activated Wnt/β-catenin signaling regulation of HepG2 cell scattering through MMP-7 transcription activation and E-cadherin degradation. The results suggest that the blocking of HGF/c-Met/β-catenin/MMP-7/E-cadherin signaling pathway might present a practical therapeutic target for interference with hepatocellular carcinoma metastasis.

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
Fig. 6

Similar content being viewed by others

References

  • Apte U, Zeng G, Muller P, Tan X, Micsenyi A, Cieply B, Dai C, Liu Y, Kaestner KH, Monga SP (2006) Activation of Wnt/beta-catenin pathway during hepatocyte growth factor-induced hepatomegaly in mice. Hepatology 44:992–1002

    Article  CAS  PubMed  Google Scholar 

  • Batlle E, Sancho E, Franc C, Domínguez D, Monfar M, Baulida J, de Herreros AG (2000) The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2:84–89

    Article  CAS  PubMed  Google Scholar 

  • Bienz M (2005) β-catenin: a pivot between cell adhesion and Wnt signalling. Curr Biol 15:R64–R67

    Article  CAS  PubMed  Google Scholar 

  • Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925

    Article  CAS  PubMed  Google Scholar 

  • Brembeck FH, Rosário M, Birchmeier W (2006) Balancing cell adhesion and Wnt signaling, the key role of β-catenin. Curr Opin Genet Dev 16:51–59

    Article  CAS  PubMed  Google Scholar 

  • Bryant DM, Stow JL (2004) The ins and outs of E-cadherin trafficking. Trends Cell Biol 14:427–434

    Article  CAS  PubMed  Google Scholar 

  • Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA, Mehra R, Laxman B, Cao X, Yu J, Kleer CG, Varambally S, Chinnaiyan AM (2008) Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27:7274–7284

    Article  CAS  PubMed  Google Scholar 

  • Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJH, Rubinfeld B, Polakis P, Matrisian LM (1999) The metalloproteinase matrilysin is a target of b-catenin transactivation in intestinal tumors. Oncogene 18:2883–2891

    Article  CAS  PubMed  Google Scholar 

  • Daugherty RL, Gottardi CJ (2007) Phospho-regulation of β-catenin adhesion and signaling functions. Physiology 22:303–309

    Article  CAS  PubMed  Google Scholar 

  • Davies G, Jiang WG, Mason MD (2001) Matrilysin mediates extracellular cleavage of E-cadherin from prostate cancer cells a key mechanism in hepatocyte growth factor/scatter factor-induced cell–cell dissociation and in vitro invasion. Clin Cancer Res 7:3289–3297

    CAS  PubMed  Google Scholar 

  • Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3:453–458

    Article  CAS  PubMed  Google Scholar 

  • Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HEM, Behrens J, Sommer T, Birchmeier W (2002) Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol 4:222–231

    Article  CAS  PubMed  Google Scholar 

  • Gao Z, Tretiakova MS, Liu W, Gong C, Farris PD, Hart J (2006) Association of E-cadherin, matrix metalloproteinases, and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma. Mod Pathol 19:533–540

    Article  CAS  PubMed  Google Scholar 

  • Grotegut S, von Schweinitz D, Christofori G, Lehembre F (2006) Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO J 25:3534–3545

    Article  CAS  PubMed  Google Scholar 

  • Gumbiner BM (2000) Regulation of cadherin adhesive activity. J Cell Biol 148:399–404

    Article  CAS  PubMed  Google Scholar 

  • Han SU, Lee HY, Lee JH, Kim WH, Nam H, Kim H, Cho YK, Kim MW, Lee KU (2005) Modulation of E-Cadherin by hepatocyte growth factor induces aggressiveness of gastric carcinoma. Ann Surg 242:676–683

    Article  PubMed  Google Scholar 

  • He TC, Zhou S, da Costa LT (1998) A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 95:2509–2514

    Article  CAS  PubMed  Google Scholar 

  • Herynk MH, Tsan R, Radinsky R, Gallick GE (2003) Activation of c-Met in colorectal carcinoma cells leads to constitutive association of tyrosine-phosphorylated β-catenin. Clin Exp Metastas 20:291–300

    Article  CAS  Google Scholar 

  • Ichikawa Y, Ishikawa T, Momiyama N, Kamiyama M, Sakurada H, Matsuyama R, Hasegawa S, Chishima T, Hamaguchi Y, Fujii S (2006) Matrilysin (MMP-7) degrades VE-cadherin and accelerates accumulation of beta-catenin in the nucleus of human umbilical vein endothelial cells. Oncol Rep 15:311–315

    CAS  PubMed  Google Scholar 

  • Ii M, Yamamoto H, Adachi Y, Maruyama Y, Shinomura Y (2006) Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Exp Biol Med 231:20–27

    CAS  Google Scholar 

  • Jiang WG, Martin TA, Parr C, Davies G, Matsumoto K, Nakamura T (2005) Hepatocyte growth factor, its receptor, and their potential value in cancer therapies. Crit Rev Oncol Hematol 53:35–69

    Article  PubMed  Google Scholar 

  • Kunio Matsumoto TN (2006) Hepatocyte growth factor and the Met system as a mediator of tumor–stromal interactions. Int J Cancer 119:477–483

    Article  PubMed  Google Scholar 

  • Lee KH, Choi EY, Hyun MS, Jang BI, Kim TN, Kim SW, Song SK, Kim JH, Kim JR (2007) Association of extracellular cleavage of E-cadherin mediated by MMP-7 with HGF-induced in vitro invasion in human stomach cancer cells. Eur Surg Res 39:208–215

    Article  CAS  PubMed  Google Scholar 

  • Leroy P, Mostov KE (2007) Slug is required for cell survival during partial epithelial–mesenchymal transition of HGF-induced tubulogenesis. Mol Biol Cell 18:1943–1952

    Article  CAS  PubMed  Google Scholar 

  • Lesko E, Majka M (2008) The biological role of HGF-MET axis in tumor growth and development of metastasis. Front Biosci 13:1271–1280

    Article  CAS  PubMed  Google Scholar 

  • Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362:1907–1917

    Article  PubMed  Google Scholar 

  • Marchenko ND, Marchenko GN, Weinreb RN, Lindsey JD, Kyshtoobayeva A, Crawford HC, Strongin AY (2004) Beta-catenin regulates the gene of MMP-26, a novel metalloproteinase expressed both in carcinomas and normal epithelial cells. Int J Biochem Cell Biol 36:942–956

    Article  CAS  PubMed  Google Scholar 

  • Munshi HG, Stack MS (2006) Reciprocal interactions between adhesion receptor signaling and MMP regulation. Cancer Metast Rev 25:45–56

    Article  CAS  Google Scholar 

  • Osada T, Sakamoto M, Ino Y, Iwamatsu A, Matsuno Y, Muto T, Hirohashi S (1996) E-cadherin is involved in the intrahepatic metastasis of hepatocellular carcinoma. Hepatology 24:1460–1467

    Article  CAS  PubMed  Google Scholar 

  • Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM (1994) A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 77:261–271

    Article  CAS  PubMed  Google Scholar 

  • Rasola A, Fassetta M, De Bacco F, D’Alessandro L, Gramaglia D, Di Renzo MF, Comoglio PM (2007) A positive feedback loop between hepatocyte growth factor receptor and bold beta-catenin sustains colorectal cancer cell invasive growth. Oncogene 26:1078–1087

    Article  CAS  PubMed  Google Scholar 

  • Sheen-Chen S-M, Liu Y-W, Eng H-L, Chou F-F (2005) Serum levels of hepatocyte growth factor in patients with breast cancer. Cancer Epiderm Biomar 14:715–717

    Article  CAS  Google Scholar 

  • Shen Y, Hirsch DS, Sasiela CA, Wu WJ (2008) Cdc42 regulates E-cadherin ubiquitination and degradation through an epidermal growth factor receptor to Src-mediatedpathway. J Biol Chem 283:5127–5137

    Article  CAS  PubMed  Google Scholar 

  • Shiota G, Okano J, Kawasaki H, Kawamoto T, Nakamura T (1995) Serum hepatocyte growth factor levels in liver diseases: clinical implications. Hepatology 21:106–112

    Article  CAS  PubMed  Google Scholar 

  • Sullivan R, Graham CH (2007) Hypoxia-driven selection of the metastatic phenotype. Cancer Metast Rev 26:319–331

    Article  CAS  Google Scholar 

  • Symowicz J, Adley BP, Gleason KJ, Johnson JJ, Ghosh S, Fishman DA, Hudson LG, Stack MS (2007) Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-Cadherin ectodomain shedding in ovarian carcinoma cells. Cancer Res 67:2030–2039

    Article  CAS  PubMed  Google Scholar 

  • Thompson EW, Newgreen DF, Tarin D (2005) Carcinoma invasion and metastasis: a role for epithelial–mesenchymal transition? Cancer Res 65:5991–5995

    Article  CAS  PubMed  Google Scholar 

  • Trusolino L, Comoglio PM (2002) Scatter-factor and semaphorin receptors: cell signaling for invasive growth. Nat Rev Cancer 2:289–300

    Article  CAS  PubMed  Google Scholar 

  • Venook AP (1994) Treatment of hepatocellular carcinoma: too many options? J Clin Oncol 12:1323–1334

    CAS  PubMed  Google Scholar 

  • von Schweinitz D, Faundez A, Teichmann B, Birnbaum T, Koch A, Hecker H, Glueer S, Fuchs J, Pietsch T (2000) Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma. Int J Cancer 85:151–159

    Google Scholar 

  • Wu B, Crampton SP, Hughes CCW (2007) Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration. Immunity 26:227–239

    Article  CAS  PubMed  Google Scholar 

  • Zavadil J, Haley J, Kalluri R, Muthuswamy SK, Thompson E (2008) Epithelial–mesenchymal transition. Cancer Res 68:9574–9577

    Article  CAS  PubMed  Google Scholar 

  • Zhang SZ, Pan FY, Xu JF, Yuan J, Guo SY, Dai G, Xue B, Shen WG, Wen CJ, Zhao DH (2005) Knockdown of c-Met by adenovirus-delivered small interfering RNA inhibits hepatocellular carcinoma growth in vitro and in vivo. Mol Cancer Ther 4:1577–1584

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Shen C. X. and Reske S. N. for their pShuttle-H1 vector. We also thank He T. C. and Vogelstein B. for their plasmid pAdEasy-1, and Dr. O. Tetsu and Dr. F. McCormick for their cDNA3 dominant negative TCF4. This work was supported by research grants from the National Natural Science Foundation of China (30800574), the Natural Science of Foundation of Jiangsu Province of China (BK2008432), the Natural Science Foundation of the Jiangsu High Education Institutions of China (07KJD180103).

Author information

Authors and Affiliations

  1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210046, China

    Fei-Yan Pan, Sheng-Zhou Zhang, Na Xu, Fan-Li Meng & Hong-Xia Zhang

  2. Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, China

    Chao-Jun Li

  3. The Medical School of Nanjing University, Nanjing, 210093, China

    Bin Xue & Chao-Jun Li

  4. College of Life Sciences, Anhui Normal University, Wuhu, 241000, China

    Sheng-Zhou Zhang

  5. Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 210029, China

    Xiao Han

Authors
  1. Fei-Yan Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sheng-Zhou Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Na Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fan-Li Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hong-Xia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bin Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chao-Jun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chao-Jun Li.

Additional information

F.-Y. Pan and S.-Z. Zhang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pan, FY., Zhang, SZ., Xu, N. et al. β-catenin signaling involves HGF-enhanced HepG2 scattering through activating MMP-7 transcription. Histochem Cell Biol 134, 285–295 (2010). https://doi.org/10.1007/s00418-010-0729-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-010-0729-3

Keywords

Search

Navigation