TY - JOUR
T1 - VILIP-1 expression in vivo results in decreased mouse skin keratinocyte proliferation and tumor development
AU - Fu, Jian
AU - Jin, Fang
AU - Zhang, Jirong
AU - Fong, Kathryn
AU - Bassi, Daniel E.
AU - de Cicco, Ricardo Lopez
AU - Ramaraju, Divya
AU - Braunewell, Karl Heinz
AU - Conti, Claudio
AU - Benavides, Fernando
AU - Klein-Szanto, Andres J.P.
PY - 2010
Y1 - 2010
N2 - VILIP-1, a member of the neuronal Ca2+ 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 ~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.
AB - VILIP-1, a member of the neuronal Ca2+ 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 ~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.
UR - http://www.scopus.com/inward/record.url?scp=77956309063&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77956309063&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0010196
DO - 10.1371/journal.pone.0010196
M3 - Article
C2 - 20419170
AN - SCOPUS:77956309063
SN - 1932-6203
VL - 5
JO - PloS one
JF - PloS one
IS - 4
M1 - e10196
ER -