VILIP-1 expression in vivo results in decreased mouse skin keratinocyte proliferation and tumor development.
VILIP-1, a member of the neuronal Ca(2+) sensor protein family, is able to act as a tumor suppressor in carcinoma cells by inhibiting cell proliferation and migration. In order to study the role of VILIP-1 in skin carcinogenesis we generated transgenic mice overexpressing VILIP-1 in epidermis under the control of the bovine keratin K5 promoter (K5-VILIP-1). We studied the susceptibility of FVB wild type and VILIP-1 transgenic mice to chemically mediated carcinogenesis. After 30 weeks of treatment with a two-stage carcinogenesis protocol, all animals showed numerous skin tumors. Nevertheless, K5-VILIP-1 mice showed decreased squamous cell carcinoma (SCC) multiplicity of approximately 49% (p<0.02) with respect to the corresponding SCC multiplicity observed in wild type (WT) mice. In addition, the relative percentage of low-grade cutaneous SCCs grade I (defined by the differentiation pattern according to the Broders grading scale) increased approximately 50% in the K5-VILIP1 mice when compared with SCCs in WT mice. Similar tendency was observed using a complete carcinogenesis protocol for skin carcinogenesis using benzo(a)pyrene (B(a)P). Further studies of tumors and primary epidermal keratinocyte cultures showed that matrix metalloproteinase 9 (MMP-9) levels and cell proliferation decreased in K5-VILIP-1 mice when compared with their wild counterparts. In addition tissue inhibitor of metalloproteinase 1 (TIMP-1) expression was higher in K5-VILIP-1 keratinocytes. These results show that VILIP-1 overexpression decreases the susceptibility to skin carcinogenesis in experimental mouse cancer models, thus supporting its role as a tumor suppressor gene.
Fu
Jian
J
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
Jin
Fang
F
Zhang
Jirong
J
Fong
Kathryn
K
Bassi
Daniel E
DE
Lopez De Cicco
Ricardo
R
Ramaraju
Divya
D
Braunewell
Karl-Heinz
KH
Conti
Claudio
C
Benavides
Fernando
F
Klein-Szanto
Andres J P
AJ
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000473:pathology; D049109:Cell Proliferation; D004198:Disease Susceptibility; D016147:Genes, Tumor Suppressor; D015603:Keratinocytes / Q000166:cytology*; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008822:Mice, Transgenic; D051596:Neurocalcin / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000209:etiology* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1; D025521:Tumor Suppressor Proteins / Q000235:genetics
D051596:Neurocalcin; D019715:Tissue Inhibitor of Metalloproteinase-1; D025521:Tumor Suppressor Proteins; C496689:Vsnl1 protein, mouse; D020780:Matrix Metalloproteinase 9