Abstract
MicroRNA (miRNA)-mediated regulation of the cellular transcriptome is an important epigenetic mechanism for fine-tuning regulatory pathways. These include processes related to skin cancer development, progression and metastasis. However, little is known about the role of microRNA as an intermediary in the carcinogenic processes following exposure to UV-radiation. We now show that UV irradiation of human primary keratinocytes modulates the expression of several cellular miRNAs. A common set of miRNAs was influenced by exposure to both UVA and UVB. However, each wavelength band also activated a distinct subset of miRNAs. Common sets of UVA- and UVB-regulated miRNAs harbor the regulatory elements GLYCA-nTRE, GATA-1-undefined-site-13 or Hox-2.3-undefined-site-2 in their promoters. In silico analysis indicates that the differentially expressed miRNAs responding to UV have potential functions in the cellular pathways of cell growth and proliferation. Interestingly, the expression of miR-23b, which is a differentiation marker of human keratinocytes, is remarkably up-regulated after UVA irradiation. Studying the interaction between miR-23b and its putative skin-relevant targets using a Luciferase reporter assay revealed that RRAS2 (related RAS viral oncogene homolog 2), which is strongly expressed in highly aggressive malignant skin cancer, to be a direct target of miR-23b. This study demonstrates for the first time a differential miRNA response to UVA and UVB in human primary keratinocytes. This suggests that selective regulation of signaling pathways occurs in response to different UV energies. This may shed new light on miRNA-regulated carcinogenic processes involved in UV-induced skin carcinogenesis.
Highlights
MicroRNAs comprise a family of small nontranslated RNAs (,19–24 nt) that are expressed in animals, plants and viruses [1,2]
In our investigation we focused on a comparison of the effect of UVA and UVB irradiation on miRNA expression 6h after UV doses (600 kJ/m2 UVA; 300 J/m2 UVB) that produce comparable levels of DNA damage in the form of cyclobutane pyrimidine dimers (6.3 arbitrary unit (a.u.) after 600 kJ/m2 UVA versus 7.5 a.u. after 300 J/m2 UVB; Fig 1)
In this study we show for the first time that there is a common miRNA response to UV accompanied by distinct wavelengthspecific miRNA responses to UVA and UVB radiation
Summary
MicroRNAs (miRNAs) comprise a family of small nontranslated RNAs (,19–24 nt) that are expressed in animals, plants and viruses [1,2]. Their primary biological action is the adjustment of protein translation through the specific regulation of target mRNAs. The association between complementary sequence motifs in the microRNA and the 3’ untranslated region (3’UTR) of target mRNAs results in the inhibition of translation [3,4] or enhanced degradation of the target mRNAs [5,6]. It has been estimated that more than 30% of the protein-coding transcriptome (mRNAs) is regulated by miRNAs [7,8]. MicroRNAs are differentially expressed in a number of tumors [12,13], including those affecting the skin [14]
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