Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Targeted inhibition of human collagenase-3 (MMP-13) expression inhibits squamous cell carcinoma growth in vivo

Oncogene volume 23, pages 5111–5123 (2004)Cite this article

Abstract

Squamous cell carcinomas (SCCs) of the head and neck are characterized by a high tendency for local invasion and metastasis to lymph nodes. Collagenase-3 (MMP-13) is specifically expressed by tumor cells in SCCs of the head and neck and its expression correlates with their invasion capacity. To specifically examine the role of MMP-13 in the growth and invasion of SCC, we constructed a hammerhead ribozyme targeted against human MMP-13 mRNA. The anti-MMP-13 ribozyme effectively cleaved MMP-13 transcripts in vitro. Adenoviral delivery of the anti-MMP-13 ribozyme to cutaneous metastatic SCC cells in culture resulted in potent and specific inhibition of the production of proMMP-13 and markedly suppressed invasion of SCC cells through Matrigel. In addition, adenoviral delivery of anti-MMP-13 ribozyme promoted apoptosis in SCC cells within 72 h. Intratumoral injection of anti-MMP-13 ribozyme coding adenovirus into human SCC xenografts established in SCID mice potently suppressed tumor growth, inhibited MMP-13 expression and gelatinolytic activity and reduced the number of proliferating cells within the tumors. These results provide evidence for an important role for MMP-13 in SCC growth and invasion and identify MMP-13 as a promising target for ribozyme-based therapy of SCC in vivo.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Abbreviations

ECM:

extracellular matrix

MMP:

matrix metalloproteinase

SCC:

squamous cell carcinoma

BrdU:

5-bromo-2-deoxyuridine

References

  • Ahonen M, Ala-aho R, Baker AH, George SJ, Grénman R, Saarialho-Kere U and Kähäri V-M . (2002). Mol. Ther., 5, 705–715.

  • Ahonen M, Poukkula M, Baker AH, Kashiwagi M, Nagase H, Eriksson JE and Kähäri V-M . (2003). Oncogene, 22, 2121–2134.

  • Airola K, Johansson N, Kariniemi A-L, Kähäri V-M and Saarialho-Kere U . (1997). J. Invest. Dermatol., 109, 225–231.

  • Airola K, Karonen T, Vaalamo M, Lehti K, Lohi J, Kariniemi AL, Keski-Oja J and Saarialho-Kere UK . (1999). Br. J. Cancer, 80, 733–743.

  • Ala-aho R, Grénman R, Seth P and Kähäri V-M . (2002a). Oncogene, 21, 1187–1195.

  • Ala-aho R, Johansson N, Baker AH and Kähäri V-M . (2002b). Int. J. Cancer, 97, 283–289.

  • Ala-aho R, Johansson N, Grénman R, Fusenig NE, López-Otín C and Kähäri V-M . (2000). Oncogene, 19, 248–257.

  • Ashworth JL, Murphy G, Rock MJ, Sherratt MJ, Shapiro SD, Shuttleworth CA and Kielty CM . (1999). Biochem. J., 340, 171–181.

  • Boström PJ, Ravanti L, Reunanen N, Aaltonen V, Söderström K-O, Kähäri V-M and Laato M . (2000). Int. J. Cancer, 88, 417–423.

  • Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A and Fusenig NE . (1988). J. Cell. Biol., 106, 761–771.

  • Boukamp P, Stanbridge EJ, Foo DY, Cerutti PA and Fusenig NE . (1990). Cancer Res., 50, 2840–2847.

  • Cazorla M, Hernandez L, Nadal A, Balbín M, López JM, Vizoso F, Fernandez PL, Iwata K, Cardesa A, López-Otín C and Campo E . (1998). J. Pathol., 186, 144–150.

  • Etoh T, Inoue H, Yoshikawa Y, Barnard GF, Kitano S and Mori M . (2000). Gut, 47, 50–56.

  • Fosang AJ, Last K, Knäuper V, Murphy G and Neame PJ . (1996). FEBS Lett., 380, 17–20.

  • Freije JM, Diéz-Itza I, Balbín M, Sánchez LM, Blasco R, Tolivia J and López-Otín C . (1994). J. Biol. Chem., 269, 16766–16773.

  • George SJ, Lloyd CT, Angelini GD, Newby AC and Baker AH . (2000). Circulation, 101, 296–304.

  • Hernandez YJ, Wang J, Kearns WG, Loiler S, Poirier A and Flotte TR . (1999). J. Virol., 73, 8549–8558.

  • Hua J and Muschel RJ . (1996). Cancer Res., 56, 5279–5284.

  • Jarvis TC, Bouhana KS, Lesch ME, Brown SA, Parry TJ, Schrier DJ, Hunt III SW, Pavco PA and Flory CM . (2000). J. Immunol., 165, 493–498.

  • Johansson N, Airola K, Grénman R, Kariniemi A-L, Saarialho-Kere U and Kähäri V-M . (1997a). Am. J. Pathol., 151, 499–508.

  • Johansson N, Saarialho-Kere U, Airola K, Herva R, Nissinen L, Westermarck J, Vuorio E, Heino J and Kähäri V-M . (1997b). Dev. Dyn., 208, 387–395.

  • Johansson N, Vaalamo M, Grénman S, Hietanen S, Klemi P, Saarialho-Kere U and Kähäri V-M . (1999). Am. J. Pathol., 154, 469–480.

  • Johansson N, Westermarck J, Leppä S, Häkkinen L, Koivisto L, López-Otín C, Peltonen J, Heino J and Kähäri V-M . (1997c). Cell Growth Differ., 8, 243–250.

  • Knäuper V, Cowell S, Smith B, López-Otín C, O'Shea M, Morris H, Zardi L and Murphy G . (1997a). J. Biol. Chem., 272, 7608–7616.

  • Knäuper V, López-Otín C, Smith B, Knight G and Murphy G . (1996). J. Biol. Chem., 271, 1544–1550.

  • Knäuper V, Smith B, López-Otín C and Murphy G . (1997b). Eur. J. Biochem., 248, 369–373.

  • Lewin AS and Hauswirth WW . (2001). Trends Mol. Med., 7, 221–228.

  • Lindy O, Konttinen YT, Sorsa T, Ding Y, Santavirta S, Ceponis A and López-Otín C . (1997). Arthritis Rheum., 40, 1391–1399.

  • Lu Y, Zhang Y and Steiner MS . (1998). DNA Cell Biol., 17, 643–645.

  • Mao D, Lee JK, VanVickle SJ and Thompson RW . (1999). Biochem. Biophys. Res. Commun., 261, 904–910.

  • McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I and Overall CM . (2001). J. Biol. Chem., 276, 43503–43508.

  • McQuibban GA, Gong JH, Tam EM, McCulloch CA, Clark-Lewis I and Overall CM . (2000). Science, 289, 1202–1206.

  • Murphy G and Knäuper V . (1997). Matrix Biol., 15, 511–518.

  • Nelson AR, Fingleton B, Rothenberg ML and Matrisian LM . (2000). J. Clin. Oncol., 18, 1135–1149.

  • Nielsen BS, Rank F, López JM, Balbin M, Vizoso F, Lund LR, Danø K and López-Otín C . (2001). Cancer Res., 61, 7091–7100.

  • Nikkola J, Vihinen P, Vlaykova T, Hahka-Kemppinen M, Kähäri V-M and Pyrhönen S . (2001). Melanoma Res., 11, 157–166.

  • Overall CM and López-Otín C . (2002). Nat. Rev. Cancer, 2, 657–672.

  • Pavco PA, Bouhana KS, Gallegos AM, Agrawal A, Blanchard KS, Grimm SL, Jensen KL, Andrews LE, Wincott FE, Pitot PA, Tressler RJ, Cushman C, Reynolds MA and Parry TJ . (2000). Clin. Cancer Res., 6, 2094–2103.

  • Ravanti L, Häkkinen L, Larjava H, Saarialho-Kere U, Foschi M, Han J and Kähäri V-M . (1999b). J. Biol. Chem., 274, 37292–37300.

  • Ravanti L, Heino J, López-Otín C and Kähäri VM . (1999a). J. Biol. Chem., 274, 2446–2455.

  • Ravanti L, Toriseva M, Penttinen R, Crombleholme T, Foschi M, Han J and Kähäri V-M . (2001). FASEB J., 15, 1098–1100.

  • Reboul P, Pelletier J-P, Tardif G, Cloutier J-M and Martel-Pelletier J . (1996). J. Clin. Invest., 97, 2011–2019.

  • Santiago FS and Khachigian LM . (2001). J. Mol. Med., 79, 695–706.

  • Sukhova GK, Schönbeck U, Rabkin E, Schoen FJ, Poole AR, Billinghurst RC and Libby P . (1999). Circulation, 99, 2503–2509.

  • Uitto V-J, Airola K, Vaalamo M, Johansson N, Putnins EE, Firth JD, Salonen J, López-Otín C, Saarialho-Kere U and Kähäri V-M . (1998). Am. J. Pathol., 152, 1489–1499.

  • Uría JA, Balbín M, López JM, Alvarez J, Vizoso F, Takigawa M and López-Otín C . (1998). Am. J. Pathol., 153, 91–101.

  • Usman N and Blatt LM . (2000). J. Clin. Invest., 106, 1197–1202.

  • Vaalamo M, Karjalainen-Lindsberg M-L, Puolakkainen P, Kere J and Saarialho-Kere U . (1998). Am. J. Pathol., 152, 1005–1014.

  • Vaalamo M, Mattila L, Johansson N, Kariniemi A-L, Karjalainen-Lindsberg M-L, Kähäri V-M and Saarialho-Kere U . (1997). J. Invest. Dermatol., 109, 96–101.

  • Vihinen P and Kähäri V-M . (2002). Int. J. Cancer, 99, 157–166.

  • Wilkinson GW and Akrigg A . (1992). Nucleic Acids Res., 20, 2233–2239.

Download references

Acknowledgements

We thank Ms Sari Pitkänen, Ms Marjo Hakkarainen, and Ms Marita Potila for skillful technical assistance. This study was supported by grants from the Academy of Finland (project 45996), Sigrid Jusélius Foundation, the Cancer Foundation of Finland, and Turku University Central Hospital (EVO13336), and by research contract with Finnish Life and Pension Insurance Companies.

Author information

Authors and Affiliations

  1. Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland

    Risto Ala-aho, Matti Ahonen & Veli-Matti Kähäri

  2. Department of Dermatology, University of Turku, Turku, FIN-20520, Finland

    Risto Ala-aho, Matti Ahonen & Veli-Matti Kähäri

  3. Centre for Biotechnology, University of Turku and Åbo Akademi University, Finland

    Risto Ala-aho, Matti Ahonen & Veli-Matti Kähäri

  4. Bristol Heart Institute, Bristol Royal Infirmary, Bristol, BS2 8HW, UK

    Sarah J George

  5. Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, FIN-20520, Finland

    Jari Heikkilä

  6. Department of Otorhinolaryngology – Head and Neck Surgery, Turku University Central Hospital, Turku, FIN-20520, Finland

    Reidar Grénman

  7. Department of Pathology, Turku University Central Hospital, Turku, FIN-20520, Finland

    Markku Kallajoki

Authors
  1. Risto Ala-aho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matti Ahonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah J George
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jari Heikkilä
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reidar Grénman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Markku Kallajoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Veli-Matti Kähäri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Veli-Matti Kähäri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ala-aho, R., Ahonen, M., George, S. et al. Targeted inhibition of human collagenase-3 (MMP-13) expression inhibits squamous cell carcinoma growth in vivo. Oncogene 23, 5111–5123 (2004). https://doi.org/10.1038/sj.onc.1207678

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207678

Keywords

This article is cited by

Search

Advanced search

Quick links