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Fu J , Jin F , Zhang J , Fong K , Bassi DE , Lopez De Cicco R , Ramaraju D , Braunewell KH , Conti C , Benavides F , Klein-Szanto AJ
VILIP-1 expression in vivo results in decreased mouse skin keratinocyte proliferation and tumor development
PLoS One. 2010 ;5(4) :e10196
PMID: 20419170    PMCID: PMC2855367   
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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 Jin, Fang Zhang, Jirong Fong, Kathryn Bassi, Daniel E Lopez De Cicco, Ricardo Ramaraju, Divya Braunewell, Karl-Heinz Conti, Claudio Benavides, Fernando Klein-Szanto, Andres J P CA06927/CA/NCI NIH HHS/United States CA107257/CA/NCI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States PloS one PLoS One. 2010 Apr 15;5(4):e10196.