Abstract
Chronic exposure to ultraviolet radiation (UVR) is linked to the development of cutaneous squamous cell carcinoma (SCC), a non-melanoma form of skin cancer that can metastasize. Tumor necrosis factor-alpha (TNFα), a pro-inflammatory cytokine, is linked to UVR-induced development of SCC. To find clues about the mechanisms by which TNFα may promote UVR-induced development of SCC, we investigated changes in the expression profiling of microRNAs (miRNA), a novel class of short noncoding RNAs, which affects translation and stability of mRNAs. In this experiment, TNFα knockout (TNFα KO) mice and their wild type (WT) littermates were exposed to acute UVR (2.0 kJ/m2) and the expression profiling of epidermal miRNA was determined 4hr post UVR exposure. TNFα deletion in untreated WT mice resulted in differential expression (log fold change>1) of seventeen miRNA. UVR exposure in WT mice induced differential expression of 22 miRNA. However, UVR exposure in TNFα KO mice altered only two miRNAs. Four miRNA, were differentially expressed between WT+UVR and TNFα KO+UVR groups. Differentially expressed selected miRNAs were further validated using real time PCR. Few of the differentially expressed miRNAs (miR-31-5p, miR-196a-5p, miR-127-3p, miR-206-3p, miR-411-5p, miR-709, and miR-322-5p) were also observed in UVR-induced SCC. Finally, bio-informatics analysis using DIANA, MIRANDA, Target Scan, and miRDB algorithms revealed a link with major UVR-induced pathways (MAPK, PI3K-Akt, transcriptional mis-regulation, Wnt, and TGF-beta).
Highlights
Ultraviolet radiation (UVR) is a potent environmental carcinogenic agent, and its chronic exposure leads to cutaneous Squamous Cell Carcinoma [1]
We found differential expression of 22 miRNAs between the wild type (WT) and WT+UVR group and 17 miRNAs between the WT and tumor necrosis factor alpha (TNFα) KO group (Tables 1, 2)
Two miRNAs were differentially expressed between TNFα knockout (TNFα KO) and TNFα KO+UVR, and four miRNAs between WT+UVR and TNFα KO+UVR groups (Table 3, 4)
Summary
Ultraviolet radiation (UVR) is a potent environmental carcinogenic agent, and its chronic exposure leads to cutaneous Squamous Cell Carcinoma (cSCC) [1]. Cutaneous SCC is the second most common non melanoma skin cancer (NMSC) with approximately 250,000 new cases per year [2]. Cutaneous SCC originates from the epidermal keratinocytes [2]. UVR exposure can directly damage the cellular DNA [3, 4]. UVR induces DNA lesions, which remains unrepaired and accumulated on replication resulting in the expansion of initiated clones. The whole process is facilitated by aberrant gene expression during initiation process of carcinogenesis. It has been observed that >60% of human protein coding genes are regulated by microRNAs (miRNAs), a novel class of regulators [5]
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