Insight into the Roles of Long Non-Coding RNAs in Ultraviolet-Induced Skin Diseases
Long non-coding RNAs (lncRNAs) are a diverse group of RNA molecules transcribed by RNA polymerase II, with lengths exceeding 200 nucleotides. Unlike protein-coding RNAs, lncRNAs do not undergo translation into proteins. Initially considered genomic “noise,” lncRNAs have now been recognized for their critical roles in regulating cellular processes and disease development. Their expression levels are generally lower than those of protein-coding genes, yet they play pivotal roles in cell differentiation, ontogeny, pathogenic infections, and immune responses. LncRNAs are categorized based on their genomic location relative to protein-coding genes, including sense, antisense, bidirectional, intronic, and intergenic lncRNAs. Their functions as signals, decoys, guides, and scaffolds in transcriptional and post-transcriptional regulation make them essential for understanding life sciences and disease mechanisms.
One of the significant areas of lncRNA research is their involvement in ultraviolet (UV)-induced skin diseases. UV radiation, particularly UVB, is a major environmental factor contributing to skin damage, photoaging, and skin cancers. LncRNAs have been implicated in mediating the cellular responses to UV radiation, influencing processes such as melanogenesis, apoptosis, inflammation, and senescence.
Lnc-CD1D-2:1 has been shown to mediate UVB-induced melanogenesis in primary melanocytes through the reactive oxygen species (ROS) pathway. This lncRNA plays a crucial role in the production of melanin, a protective pigment in the skin. Another set of lncRNAs, GS1-600G8.5 and RP13-631K18.2, are upregulated specifically by UVA exposure. GS1-600G8.5, in particular, regulates interleukin-8 (IL-8) expression, a key cytokine involved in inflammation. Knockdown of GS1-600G8.5 results in decreased IL-8 mRNA expression and secretion, highlighting its role in the inflammatory response to UV radiation.
LincRNA-p21 is a major mediator of UVB-induced, p53-dependent apoptosis in keratinocytes (KCs). This lncRNA is crucial for the programmed cell death response to UVB damage, ensuring the removal of severely damaged cells to prevent carcinogenesis. Similarly, lncRNA AC005779.1 is significantly upregulated in UVB-irradiated KCs, although its specific functional role remains to be fully elucidated.
LncRNA HULC enhances UV-induced damage in HaCaT cells by upregulating BNIP3, which activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. This pathway is involved in various cellular responses, including apoptosis and inflammation, making HULC a potential target for therapeutic intervention.
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is another important lncRNA in UV-induced skin damage. MALAT1 expression is increased in dermal fibroblasts following UVB radiation, contributing to photoaging and senescence. Interestingly, MALAT1 expression is cell-type specific, as it is not altered in KCs by UVB radiation. MALAT1 regulates the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway in a ROS-independent manner, influencing cell migration and senescence. Knockdown of MALAT1 reduces cell migration in human melanoma cells (A375 cell lines), indicating its role in cancer progression.
HOTAIR (HOX transcript antisense RNA) is the first lncRNA identified to have a trans-acting effect. It is widely involved in the regulation of malignant processes, including proliferation, apoptosis, angiogenesis, invasion, and metastasis. HOTAIR modulates epigenetic modifications through histone H3K27me3 and regulates Wnt inhibitory factor 1 and phosphatase and tensin homolog (PTEN), affecting the Wnt and Akt signaling pathways. In KCs, overexpression of HOTAIR upregulates protein kinase R (PKR) expression, activating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and nuclear factor kappa-B (NF-kB) pathways, promoting UVB-induced apoptosis and inflammatory injury.
TINCR (terminal differentiation-induced non-coding RNA) is essential for epidermal differentiation. Deficiency in TINCR results in the absence of terminal differentiation ultrastructure, keratohyalin granules, and normal keratin hyaluronan granule formation. TINCR also plays a key role in suppressing tumor formation in squamous cell carcinoma. A balance between anti-differentiation lncRNA (lncRNA-ANCR) and TINCR levels is crucial for epidermal cell differentiation. ANCR maintains progenitor cells in their undifferentiated state, while TINCR promotes terminal differentiation.
Growth-arrested DNA damage-inducible gene 7 (GADD7) is a DNA damage-inducible lncRNA involved in cell cycle regulation at the G1/S checkpoint. It modulates mRNA expression post-transcriptionally by altering mRNA stability. Psoriasis associated RNA induced by stress (PRINS) plays a role in the cellular stress response in the skin. RP11-670E13.6 delays cellular senescence in UVB-damaged human dermal fibroblasts through the p16-pRB pathway and binds directly to miR663a to modulate the derepression of Cdk4 and Cdk6 via a competing endogenous RNA (ceRNA) mechanism.
H19, the first lncRNA discovered, is located on human chromosome 11p15.5 and forms the H19/insulin-like growth factor 2 (IGF-2) imprinted gene group. H19 is involved in melanosome transfer and may be related to the pathogenesis of melasma. In endothelial cells, the mitochondrial lncRNA ASncmtRNA-2 contributes to replicative senescence via cell cycle arrest in the G2/M phase. TUG1 promotes apoptosis in lens epithelial cells by downregulating miR-421 expression via the caspase-3 axis, highlighting its role in age-related cataract formation.
In conclusion, lncRNAs are superior disease biomarkers with significant transcriptional and post-transcriptional regulatory roles. They are vital for understanding cellular processes and disease development, including cell differentiation, ontogeny, pathogenic infections, and immune responses. LncRNAs act as signals, decoys, guides, and scaffolds in gene expression regulation, making their study essential for advancing life sciences. However, the pathways, targets, and regulatory mechanisms of lncRNAs in UV-induced diseases are not yet fully understood. Further research is needed to elucidate these mechanisms and develop targeted therapies for the prevention and treatment of skin diseases. In vivo studies and clinical trials are necessary to validate the findings from in vitro experiments and translate them into effective treatments.
doi.org/10.1097/CM9.0000000000001062
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