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

• Published in: Oncogene Vol. 23; no. 30; pp. 5111 - 5123
• Main Authors: ALA-AHO, Risto, AHONEN, Matti, GEORGE, Sarah J, HEIKKILÄ, Jari, GRENMAN, Reidar, KALLAJOKI, Markku, KÄHÄRI, Veli-Matti
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 01.07.2004; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Adenovirus; Adenoviruses; Animals; Apoptosis; Biochemistry; Biological and medical sciences; Cancer; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - pathology; Cell culture; Cell Division; Cell physiology; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Collagen; Collagen - metabolism; Collagen - pharmacology; Collagenase; Collagenase 3; Collagenases - genetics; Collagenases - metabolism; Drug Combinations; Esophagus; Fundamental and applied biological sciences. Psychology; Gelatinases - metabolism; Gene expression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Head and neck carcinoma; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - pathology; Humans; Immunohistochemistry; Keratinocytes - cytology; Keratinocytes - enzymology; Laminin; Lymph nodes; Male; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Metastases; Metastasis; Mice; Mice, SCID; Molecular and cellular biology; Molecular biology; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Otolaryngology; Proteoglycans; RNA, Messenger - genetics; Squamous cell carcinoma; Time Factors; Tumor cells; Tumor Cells, Cultured; Tumors; Xenografts; Finland; Human; Squamous cell carcinoma; Ribozyme; Enzyme; Growth; Metalloendopeptidases; Malignant tumor; Metastasis; Gene expression; Carcinogenesis; Invasion; Peptidases; In vivo; collagenase; Treatment; Hydrolases; Inhibition; Interstitial collagenase
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207678

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.