Abstract 4204: Chronic ultraviolet radiation exposure of mouse skin activates GATA and PAX families of transcription factors, which regulate expression of cell survival genes

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Chronic exposure to ultraviolet radiation (UVR) is the most common etiologic factor linked to the development of squamous cell carcinoma (SCC), a non-melanoma form of skin cancer that can metastasize. UVR-induced development of SCC has been shown to be associated with activation of transcription factors Stat3, AP-1 and NF-κB. Here, we report the activation of several novel transcription factors (TFs) following exposure of mouse skin to UVR. In this experiment, FVB/N mice were exposed to UVR (2kj/m2) four times (Monday, Wednesday, Friday and Monday). At 1hr and 3hrs post last UVR exposure, these mice were sacrificed. Nuclear lysates were prepared from the scraped epidermis of these mice. To screen for unknown TFs, we employed the Panomics Combo Protein/DNA array, which contains consensus complimentary sequences of 345 TFs binding sites. Array data was analyzed according to the vendor's suggestions. TFs spots that show more than two fold induction were scored as positive for activation. We observed activation of 70 TFs as early as 1hr post UVR exposure. Twenty four TFs (GATA-1, GATA-2, Thy-1BP, AhR/Amt, Sp-1, HFH-2, HFH-3, HIF-1, CEF-2, TEF-1, PU-1, c-Rel, E47, Anti-oxidant-RE, HOXD8/9/10, PAX-4, LH-2/lim-1, NF-4FA, NCAM BP, WTI, E12, EBP40/45, CEA, MUSF) were activated compared to unexposed mice. Forty six out of seventy were new TFs, which were absent in unexposed mice. These were MHC W box, MT Box, Freac-2, CTCF, MyoD, KBF-A, PPAR, HOXD9/10, Myb, RSRFC4, PYR, WTI, MZF, SAA, COUP-TF, CCAC, EGR, E2F-1, NF-E1/YY-1, NF-1, NF-1/L, PAX-1, PAX-2, PAX-8, PAX-6, NF-ATp, CEBP, AAF, HMG, ADD-1, L-IIIBP, GATA-6, Ets, AP-3, KKLF, HNF-1A, Lyf, EGR-1, XBP-1, HFH-1, Surf-1, YB-1, Fast-1, MSP-1, PPUR, T3R. Among all seventy TFs, highly activated TFs were GATA-1, GATA-2, PAX-4, PAX-6, PAX-8, Thy-1BP, HFH-2, HFH-3, HIF-1, CEA, HOD8/9/10, AhR/Amt, and MUSF. Literature search revealed that there is no report about the role of these TFs in UVR-induced skin carcinogenesis. We employed the Genego program to determine the downstream target genes for all these TFs and found that VEGFR-2, CyclinD1, Bcl-2, Bcl-xl, p53, c-Myc, BMP-4, WT1, survivin are the downstream target genes of GATA1, GATA-2, PAX-4 and PAX-8. All these genes have been shown for their role in anti-apoptosis, cell survival and metastasis of various types of cancers including skin. Importantly, we also observed activation of PAX-8 in UVR exposed mice, which inhibits the transcriptional activation of the tumor suppressor p53 gene. Evidence indicates that GATA-1 controls the expressions of miRNA-144 and miRNA-451. Other study has been shown that inhibition of miRNA-144 causes a decrease in proliferation of Hela cells. We conclude that GATA and PAX family of TFs may have an important role in UVR-induced skin carcinogenesis via modulation of various downstream target genes and microRNAs. (Support: RO1CA35368). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4204. doi:10.1158/1538-7445.AM2011-4204