Squamous cell carcinoma growth in mice and in culture is regulated by c-Jun and its control of matrix metalloproteinase-2 and -9 expression.
Squamous cell carcinoma (SCC) is an invasive malignancy of epidermal keratinocytes. Surgical excision is currently the main treatment; however, this can cause scarring and disfigurement. There is accordingly, an acute need for alternative strategies to treat SCC. The transcription factor c-Jun is expressed in human SCC and another common form of invasive skin cancer, basal cell carcinoma together with the mitogenic marker-proliferating cell nuclear antigen. Here, we have employed DNAzymes (catalytic DNA molecules) targeting c-Jun (Dz13) to inhibit c-Jun expression in SCC cells. Dz13 inhibits SCC proliferation and suppresses solid SCC tumor growth and tumor angiogenesis in severe combined immunodeficient mice. We further demonstrate that Dz13 inhibits c-Jun, together with matrix metalloproteinase (MMP)-2 and MMP-9 expression in the tumors, consistent with DNAzyme inhibition of MMP-2 and MMP-9 gelatinolytic activity by zymography. Dz13 also suppressed the expression of vascular endothelial growth factor and fibroblast growth factor-2 in the tumors. These findings demonstrate that c-Jun regulates SCC growth and suggest that DNAzymes targeting this transcription factor may potentially be useful as inhibitors of cutaneous carcinoma.
Zhang
G
G
Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.
Luo
X
X
Sumithran
E
E
Pua
V S C
VS
Barnetson
R St C
RS
Halliday
G M
GM
Khachigian
L M
LM
D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D021881:DNA, Catalytic / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016513:Mice, SCID; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000502:physiology*
D021881:DNA, Catalytic; D061965:Matrix Metalloproteinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9