Abstract
Abstract 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. To find clues about the mechanism of UVR-induced development of SCC in FVB/N mice, we found that chronic UVR exposures lead to aberrant expression of several microRNAs (miRNAs). In the present experiment, mice were exposed to four (Monday, Wednesday, Friday and Monday) UVR (2 kJ/m2) treatments, emitted by Kodacel-filtered FS-40 sun lamps (approximately 60% UVB and 40% UVA). At 3 hrs post last UVR exposure, mice were sacrificed. RNAs were prepared from the scraped epidermis of these mice. To screen for unknown miRNAs, we performed the 1040 miRNAs microarray analysis. UVR treatment resulted in modulation of 15 miRNAs: six miRNAs (miR-145, miR-1937a, miR-1937b, miR-341*, miR-451, miR-720) were up-regulated while nine miRNAs (let-7g, miR-125–5p, miR-195, miR-200b, miR-29a, miR-30c, miR-429, miR-92a) were down-regulated. The microarray results were further validated by qRT-PCR. These UVR-induced over-expressed (e.g; miR-451) and down-regulated (e.g; let-7g, miR-195) miRNAs have been observed to be oncogene and tumor suppressor, respectively in various types of cancers. To determine the downstream target genes (DTG) of these miRNAs, insilico analysis was performed. We employed the DIANA LAB DNA Intelligent and Target-Scan program to reveal the various pathways and genes regulated by these miRNAs. Finally we did the IPA to decipher the existing network between these target genes. Among all the miRNAs modulated by UVR treatment, only miR-429 and miR-195 shown to have significant network. MiR-429 network consist of few important hubs. Those were TARDBP, PCBP (Poly (rC) Binding Protein) and PUF60. TARDBP is reported to bind to chromosomally integrated TAR DNA and repress HIV transcription. PCBP1 and PCBP2 are multifunctional protein reported to be translational coactivator. PUF60 is known as a transcriptional repressor. The network obtained by miR-195 DTG revealed that various cytokines exist in the downstream network. Among them, IL-10, IFN-γ and TNF-α are the most significant hub of the network. We also found ZFP36 as an important hub, which is known for recruiting the miRNA at the 3′UTR of mRNA. IPA analysis suggests that all of the above hub molecules play major roles in cell cycle and cancer initiation and progression. UVR-induced deregulated miRNAs (miR-145, miR-1937a, miR-1937b, miR-341*, miR-451, miR-720 – let-7g, miR-125–5p, miR-195, miR-200b, miR-29a, miR-30c, miR-429, miR-92a) may constitute important components of UVR carcinogenesis (Support: NIH grant CA35368). 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 LB-343. doi:10.1158/1538-7445.AM2011-LB-343
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