Targeted inhibition of human collagenase-3 (MMP-13) expression inhibits squamous cell carcinoma growth in vivo.
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.
Ala-aho
Risto
R
Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland.
Ahonen
Matti
M
George
Sarah J
SJ
Heikkilä
Jari
J
Grénman
Reidar
R
Kallajoki
Markku
M
Kähäri
Veli-Matti
VM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D018093:Gelatinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology; D007797:Laminin; D008297:Male; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011509:Proteoglycans; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004338:Drug Combinations; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D011509:Proteoglycans; D012333:RNA, Messenger; C059485:matrigel; D003094:Collagen; D017364:Collagenases; D018093:Gelatinases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse