Project 2 addresses the later events in skin cancer development leading to malignant conversion and an approach to therapy. We show that molecular profiling produces a signature of gene expression that distinguishes between benign tumors at low and high risk for premalignant progression. This gene list allowed us to determine the progression risk for a group of unknown samples. We also determined that CLIC4 can serve as a marker for progression of a variety of human and experimental cancers. As cancers progress, CLIC4 is lost from the cancer cells and induced in stromal cells. The stromal change is associated with fibroblast to myofibroblast conversion and is convergent with the induction of alpha smooth muscle actin. Overexpression of exogenous CLIC4 in tumor cells in vivo inhibits tumor growth while overexpression of exogenous CLIC4 in stromal cells enhances tumor growth. Mechanistic studies suggest that nuclear CLIC4 participates in the TGF beta pathway through interactions with Schnurri 2 and Smads. Finally, we report that a protein kinase C activator in clinical trials for the treatment of skin cancer induces a hemorrhagic necrosis through interactions with immunophilins.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005445-22
Application #
7337852
Study Section
(LCCT)
Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Mascia, Francesca; Schloemann, Derek T; Cataisson, Christophe et al. (2016) Cell autonomous or systemic EGFR blockade alters the immune-environment in squamous cell carcinomas. Int J Cancer 139:2593-7
Wright, Lisa Nolan; Ryscavage, Andrew; Merlino, Glenn et al. (2012) Modeling the transcriptional consequences of epidermal growth factor receptor ablation in Ras-initiated squamous cancer. Clin Cancer Res 18:170-83
Wolf, Ronald; Voscopoulos, Christopher; Winston, Jason et al. (2009) Highly homologous hS100A15 and hS100A7 proteins are distinctly expressed in normal breast tissue and breast cancer. Cancer Lett 277:101-7
Cataisson, Christophe; Ohman, Rebecca; Patel, Gopal et al. (2009) Inducible cutaneous inflammation reveals a protumorigenic role for keratinocyte CXCR2 in skin carcinogenesis. Cancer Res 69:319-28
Park, Jung-Eun; Li, Luowei; Park, Joobae et al. (2009) Direct quantification of polo-like kinase 1 activity in cells and tissues using a highly sensitive and specific ELISA assay. Proc Natl Acad Sci U S A 106:1725-30
Scortegagna, Marzia; Cataisson, Christophe; Martin, Rebecca J et al. (2008) HIF-1alpha regulates epithelial inflammation by cell autonomous NFkappaB activation and paracrine stromal remodeling. Blood 111:3343-54
Wolf, Ronald; Howard, O M Zack; Dong, Hui-Fang et al. (2008) Chemotactic activity of S100A7 (Psoriasin) is mediated by the receptor for advanced glycation end products and potentiates inflammation with highly homologous but functionally distinct S100A15. J Immunol 181:1499-506
Suh, Kwang S; Malik, Mariam; Shukla, Anjali et al. (2007) CLIC4, skin homeostasis and cutaneous cancer: surprising connections. Mol Carcinog 46:599-604
Darwiche, N; Ryscavage, A; Perez-Lorenzo, R et al. (2007) Expression profile of skin papillomas with high cancer risk displays a unique genetic signature that clusters with squamous cell carcinomas and predicts risk for malignant conversion. Oncogene 26:6885-95
Gerdes, Michael J; Myakishev, Maxim; Frost, Nicholas A et al. (2006) Activator protein-1 activity regulates epithelial tumor cell identity. Cancer Res 66:7578-88

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