Using differential display and other molecular techniques we identified the absence of expression of a gene homologous to the human Visinin-like Protein 1 (VILIP-1) in selected high grade murine squamous cell carcinoma (SCC) and in tumor cell lines. Ectopic expression of VILIP-1 in SCC cell lines resulted in a less aggressive phenotype associated with increased levels of cAMP, decreased cell proliferation and decreased RhoA activation. The central hypothesis to be tested in vivo is that the loss of VILIP-1 expression enhances the malignant phenotype of SCC cells by down-regulating cyclic nucleotide-dependent pathways that include specific tumor-progression-related targets, such as small GTPases, thus constituting an important element in the chain of events leading to the malignant phenotype. Conversely, VILIP-1 expression should increase resistance to skin carcinogenesis by decreasing tumor cell growth and/or inhibiting tumor progression. For this purpose we have designed three specific aims: 1) Examine biological and biochemical mechanisms whereby loss of VILIP-1 expression may lead to increased malignancy. In this experiment, we will study cell proliferation, differentiation, adhesiveness, migration and invasiveness of VILIP-1 transfectants and knocked-down SCC cells in the context of cyclic nucleotide regulation. We will focus on the relative hierarchical role played by cAMP and cGMP, both known to be regulated by VILIP-1, and their participation as possible effectors of small GTPases. 2) We will evaluate the in vivo susceptibility to carcinogenesis in K5-VILIP-1 transgenic mice. These mice should be less susceptible to skin chemical carcinogenesis and will be utilized to evaluate in vivo the mechanism of action of VILIP-1. 3) Investigate the in vivo susceptibility to skin carcinogenesis using a protocol of ultraviolet carcinogenesis in K5-VILEP-1 transgenic mice backcrossed to a SHK-1 background. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA107257-01A2
Application #
6993466
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Yang, Shen K
Project Start
2005-08-01
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$303,953
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
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Schönrath, Katharina; Pan, Wensheng; Klein-Szanto, Andres J et al. (2011) Involvement of VILIP-1 (visinin-like protein) and opposite roles of cyclic AMP and GMP signaling in in vitro cell migration of murine skin squamous cell carcinoma. Mol Carcinog 50:319-33
Fu, Jian; Jin, Fang; Zhang, Jirong et al. (2010) VILIP-1 expression in vivo results in decreased mouse skin keratinocyte proliferation and tumor development. PLoS One 5:e10196
Fu, Jian; Zhang, Jirong; Jin, Fang et al. (2009) Promoter regulation of the visinin-like subfamily of neuronal calcium sensor proteins by nuclear respiratory factor-1. J Biol Chem 284:27577-86
Braunewell, Karl-Heinz; Klein-Szanto, Andres J; Szanto, Andres J Klein (2009) Visinin-like proteins (VSNLs): interaction partners and emerging functions in signal transduction of a subfamily of neuronal Ca2+ -sensor proteins. Cell Tissue Res 335:301-16
Fu, Jian; Fong, Kathryn; Bellacosa, Alfonso et al. (2008) VILIP-1 downregulation in non-small cell lung carcinomas: mechanisms and prediction of survival. PLoS One 3:e1698
Wickborn, Carla; Klein-Szanto, Andres J; Schlag, Peter M et al. (2006) Correlation of visinin-like-protein-1 expression with clinicopathological features in squamous cell carcinoma of the esophagus. Mol Carcinog 45:572-81