title: Squamous cell carcinoma growth in mice and in culture is regulated by c-Jun and its control of matrix metalloproteinase-2 and -9 expression.
abstract: 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.
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.forename: E
authors.initials: E
authors.lastname: Sumithran
authors.forename: V S C
authors.initials: VS
authors.lastname: Pua
authors.forename: R St C
authors.initials: RS
authors.lastname: Barnetson
authors.forename: G M
authors.initials: GM
authors.lastname: Halliday
authors.forename: L M
authors.initials: LM
authors.lastname: Khachigian
mesh_terms: 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*
chemical_list: D021881:DNA, Catalytic; D061965:Matrix Metalloproteinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9