UV-induced Changes Research Articles

OP-28 - A novel role for NUPR1 in the keratinocyte stress response to UV oxidized phospholipids

Ultraviolet light is the dominant environmental oxidative skin stressor and a major factor in skin aging. We studied which oxidized phospholipid (OxPL) species would be generated in primary human keratinocytes (KC) upon exposure to ultraviolet A light (UVA) and investigated the contribution of OxPL to UVA responses. Mass spectrometric analysis revealed dynamic UV-induced changes in abundance of 174 lipid species within 24 hours. We identified known and novel bioactive and also chemically reactive lipids and found indication for selective degradation of selected reactive lipid classes. Exposure to both UVA and to in vitro UVA - oxidized phospholipids activated, on transcriptome and proteome level, NRF2/antioxidant response signaling, lipid metabolizing enzyme expression and unfolded protein response signaling. We further identified NUPR1 as an upstream regulator of UVA/OxPL transcriptional responses and found this protein expressed in the epidermis and permissive to modification by oxidized lipids. Silencing of NUPR1 resulted in augmented expression of antioxidant and lipid detoxification genes and disturbed the cell cycle, making it a potential key factor in skin reactive oxygen species (ROS) responses intimately involved in aging and pathology.

Pharmacological TLR4 Antagonism Using Topical Resatorvid Blocks Solar UV-Induced Skin Tumorigenesis in SKH-1 Mice.

An urgent need exists for the development of more efficacious molecular strategies targeting nonmelanoma skin cancer (NMSC), the most common malignancy worldwide. Inflammatory signaling downstream of Toll-like receptor 4 (TLR4) has been implicated in several forms of tumorigenesis, yet its role in solar UV-induced skin carcinogenesis remains undefined. We have previously shown in keratinocyte cell culture and SKH-1 mouse epidermis that topical application of the specific TLR4 antagonist resatorvid (TAK-242) blocks acute UV-induced AP-1 and NF-κB signaling, associated with downregulation of inflammatory mediators and MAP kinase phosphorylation. We therefore explored TLR4 as a novel target for chemoprevention of UV-induced NMSC. We selected the clinical TLR4 antagonist resatorvid based upon target specificity, potency, and physicochemical properties. Here, we confirm using ex vivo permeability assays that topical resatorvid can be effectively delivered to skin, and using in vivo studies that topical resatorvid can block UV-induced AP-1 activation in mouse epidermis. We also report that in a UV-induced skin tumorigenesis model, topical resatorvid displays potent photochemopreventive activity, significantly suppressing tumor area and multiplicity. Tumors harvested from resatorvid-treated mice display reduced activity of UV-associated signaling pathways and a corresponding increase in apoptosis compared with tumors from control animals. Further mechanistic insight on resatorvid-based photochemoprevention was obtained from unsupervised hierarchical clustering analysis of protein readouts via reverse-phase protein microarray revealing a significant attenuation of key UV-induced proteomic changes by resatorvid in chronically treated high-risk SKH-1 skin prior to tumorigenesis. Taken together, our data identify TLR4 as a novel molecular target for topical photochemoprevention of NMSC. Cancer Prev Res; 11(5); 265-78. ©2018 AACRSee related editorial by Sfanos, p. 251.

UV-Induced Hydrogen-Atom-Transfer Processes in 3-Thio-1,2,4-triazole Isolated in Ar and H2 Low-Temperature Matrixes.

The UV-induced thione → thiol phototautomeric reaction has been studied for monomeric 3-thio-1,2,4-triazole (3-ST) isolated in low-temperature Ar and n-H2 (normal hydrogen) matrixes. Prior to any UV irradiation, monomers of 3-ST isolated in solid Ar or solid n-H2 adopted mainly the most stable thione tautomeric form, as revealed by the IR spectra. Upon UV (λ > 275 nm) irradiation of 3-ST isolated in Ar matrixes, the IR bands due to this thione form decreased, while a set of initially weak bands increased in intensity. Growing bands indicated generation of a photoproduct, which was identified as the thiol tautomer with labile hydrogen atoms attached to sulfur and N(2) atoms. The UV-induced spectral changes allowed also identification of another minor thiol tautomer of 3-ST, which was present in the matrix prior to any irradiation and did not change its population upon exposure to UV light. The identification of the observed isomeric forms was supported by comparison of their separated experimental IR spectra with the spectra theoretically predicted for the various structures of 3-ST. The thione → thiol phototautomerization that was the main UV-induced process observed for 3-ST in Ar matrixes did not occur for monomers of the compound trapped in solid n-H2.

P 103 - Proteomic analysis of rutin effect on human skin fibroblasts exposed to UVA or UVB irradiation

Rutin, due to its polyphenolic structure reveals antioxidant properties and may be used as a cytoprotective compound against UV-induced effects on skin cells. Therefore, the aim of this study was to examine the rutin effects on UV-induced changes in proteome profile of human skin fibroblasts cultured in vitro. PCA analysis of results obtained by QExactive OrbiTrap mass spectrometer show clear differentiation only between control and UVA treated cells, although significant changes in the individual proteins level are also observed between the rest of tested fibroblast groups. Rutin treatment prevents UVA-induced, even 2-fold, increase in the total expression of proteins involved in antioxidant (e.g. superoxide dismutases, disulfide isomerase) and inflammatory response (e.g. IL-17, PAK2, YWHAZ), what is not observed in fibroblasts after rutin treatment following UVB irradiation. However, rutin treatment of fibroblasts after UVB radiation promotes rutin-Keap1 adducts formation thus activation of Nrf2 - responsible for cytoprotective proteins synthesis. Rutin also prevents UV-induced apoptosis, through restoring the pro-apoptotic proteins level (e.g. p53 and cytochrome c) that is enhanced after the irradiation. In conclusion, our results show that rutin effectively prevents UV-induced damages associated with proinflammatory/prooxidative and proapoptotic activity.

Crosstalk Among UV-Induced Inflammatory Mediators, DNA Damage and Epigenetic Regulators Facilitates Suppression of the Immune System.

The suppression of the immune system by overexposure to ultraviolet (UV) radiation has been implicated in the initiation and progression of photocarcinogenesis. Numerous changes occur in the skin on UVB exposure, including the generation of inflammatory mediators, DNA damage, epigenetic modifications, and migration and functional alterations in the antigen-presenting dendritic cells. Although each of these alterations can elicit a cascade of events that have the potential to modulate immune sensitivity alone, there is emerging evidence that there is considerable crosstalk between these cascades. The development of an understanding of UV-induced changes in the skin that culminate in UV-induced immunosuppression, which has been implicated in the risk of nonmelanoma skin cancer, as a network of events has implications for the development of more effective chemopreventive strategies. In the current review article, we discuss the evidence of interactions between the various molecular targets and signaling mechanisms associated with UV-induced immunosuppression.

Rutin as a Mediator of Lipid Metabolism and Cellular Signaling Pathways Interactions in Fibroblasts Altered by UVA and UVB Radiation.

Background. Rutin is a natural nutraceutical that is a promising compound for the prevention of UV-induced metabolic changes in skin cells. The aim of this study was to examine the effects of rutin on redox and endocannabinoid systems, as well as proinflammatory and proapoptotic processes, in UV-irradiated fibroblasts. Methods. Fibroblasts exposed to UVA and UVB radiation were treated with rutin. The activities and levels of oxidants/antioxidants and endocannabinoid system components, as well as lipid, DNA, and protein oxidation products, and the proinflammatory and pro/antiapoptotic proteins expression were measured. Results. Rutin reduced UV-induced proinflammatory response and ROS generation and enhanced the activity/levels of antioxidants (SOD, GSH-Px, vitamin E, GSH, and Trx). Rutin also normalized UV-induced Nrf2 expression. Its biological activity prevented changes in the levels of the lipid mediators: MDA, 4-HNE, and endocannabinoids, as well as the endocannabinoid receptors CB1/2, VR1, and GPR55 expression. Furthermore, rutin prevented the protein modifications (tyrosine derivatives formation in particular) and decreased the levels of the proapoptotic markers—caspase-3 and cytochrome c. Conclusion. Rutin prevents UV-induced inflammation and redox imbalance at protein and transcriptional level which favors lipid, protein, and DNA protection. In consequence rutin regulates endocannabinoid system and apoptotic balance.

UV radiation impacts body weight, oxygen consumption, and shelter selection in the intertidal vertebrate Girella laevifrons

The amount of ultraviolet (UV) radiation reaching the earth's surface has increased due to ozone layer depletion, and this fact represents an opportunity to evaluate the physiological and behavioral responses of animals to this global-scale stressor. The transitory fish Girella laevifrons inhabits pools in the upper intertidal zone, which is characterized by exposure to a wide range of stressors, including UV radiation. We documented the field magnitude and the impact of UV radiation on oxygen consumption, body mass variations, and shelter (rocky and algae) selection by G. laevifrons. UV-exposed animals showed increased oxygen consumption, slower body weight increase, and active rocky shelter selection. Control fish showed increased body weight and no evident shelter selection. The results indicated that UV exposure affects fish energetic balance and habitat selection to favor greater protection against radiation. Increased UV exposure in transitory intertidal animals at levels observed in upper intertidal pools may alter the residency time of fish before leaving for the subtidal zone. Therefore, UV-induced energetic changes may determine animal performance and ontogenetic physiological itineraries, whereas shelter quality might determine habitat use.

The interaction of inulinase molecules with a chitosan matrix: UV-induced changes in the functional properties of immobilized inulinase

We have developed a technique for the immobilization of inulinase on chitosans with different molecular weights. The acid-soluble mid-molecular-weight (200 kDa) and high-molecular-weight (350 kDa) chitosans are shown to be promising matrices for inulinase adsorption. We assumed that the formation of an inulinase-chitosan matrix complex occurs mainly due to hydrophobic interactions; electrostatic interactions also play an essential role. The enzyme complex with high-molecular-weight chitosan is more stable against the action of UV light and temperature. This allows us to recommend chitosan as a catalyst in industry for the production of fructose from inulin-containing vegetable raw mateials.

Tuning the Band Bending and Controlling the Surface Reactivity at Polar and Nonpolar Surfaces of ZnO through Phosphonic Acid Binding.

ZnO is a prime candidate for future use in transparent electronics; however, development of practical materials requires attention to factors including control of its unusual surface band bending and surface reactivity. In this work, we have modified the O-polar (0001̅), Zn-polar (0001), and m-plane (101̅0) surfaces of ZnO with phosphonic acid (PA) derivatives and measured the effect on the surface band bending and surface sensitivity to atmospheric oxygen. Core level and valence band synchrotron X-ray photoemission spectroscopy was used to measure the surface band bending introduced by PA modifiers with substituents of opposite polarity dipole moment: octadecylphosphonic acid (ODPA) and 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctylphosphonic acid (F13OPA). Both PAs act as surface electron donors, increasing the downward band bending and the strength of the two-dimensional surface electron accumulation layer on all of the ZnO surfaces investigated. On the O-polar (0001̅) and m-plane (101̅0) surfaces, the ODPA modifier produced the largest increase in downward band bending relative to the hydroxyl-terminated unmodified surface of 0.55 and 0.35 eV, respectively. On the Zn-polar (0001) face, the F13OPA modifier gave the largest increase (by 0.50 eV) producing a total downward band bending of 1.00 eV, representing ∼30% of the ZnO band gap. Ultraviolet (UV) photoinduced surface wettability and photoconductivity measurements demonstrated that the PA modifiers are effective at decreasing the sensitivity of the surface toward atmospheric oxygen. Modification with PA derivatives produced a large increase in the persistence of UV-induced photoconductivity and a large reduction in UV-induced changes in surface wettability.

Transcriptome Analysis Identifies the Dysregulation of Ultraviolet Target Genes in Human Skin Cancers

Exposure to ultraviolet radiation (UVR) is a major risk factor for both melanoma and non-melanoma skin cancers. In addition to its mutagenic effect, UVR can also induce substantial transcriptional instability in skin cells affecting thousands of genes, including many cancer genes, suggesting that transcriptional instability may be another important etiological factor in skin photocarcinogenesis. In this study, we performed detailed transcriptomic profiling studies to characterize the kinetic changes in global gene expression in human keratinocytes exposed to different UVR conditions. We identified a subset of UV-responsive genes as UV signature genes (UVSGs) based on 1) conserved UV-responsiveness of this subset of genes among different keratinocyte lines; and 2) UV-induced persistent changes in their mRNA levels long after exposure. Interestingly, 11 of the UVSGs were shown to be critical to skin cancer cell proliferation and survival. Through computational Gene Set Enrichment Analysis, we demonstrated that a significant portion of the UVSGs were dysregulated in human skin squamous cell carcinomas, but not in other human malignancies. This highlights the potential and specificity of the UVSGs in clinical diagnosis of UV damage and stratification of skin cancer risk.

Cross-talk between interferon-gamma and interleukin-18 in melanogenesis

Skin is the largest organ in our body and strategically placed to provide a metabolically active biological barrier against a range of noxious stressors. A lot of inflammatory cytokines, which are increased after ultraviolet (UV) irradiation produced by keratinocytes or other immunocytes, are closely related to pigmentary changes, including interleukin-18 (IL-18) and interferon-γ (IFN-γ). In this study, the effect of cross-talk between IL-18 and IFN-γ on melanogenesis was investigated. Treatment with IL-18 resulted in a dose-dependent increase of melanogenesis, while IFN-γ made an opposite effect. This influence of IL-18 and IFN-γ was mediated by regulations of microphthalmia-associated transcription factor (MITF) and its downstream enzymatic cascade expressions. Furthermore, IFN-γ inhibited basal and IL-18-induced melanogenesis. IFN-γ increased signal transducer and activator of transcription-1 (STAT-1) phosphorylation to play its position in regulating melanin pigmentation, and its inhibitory effect could be prevented by Janus Kinase 1 (JAK 1) inhibitor. IFN-γ could inhibit melanogenesis by decreasing melanocyte dendrite formation. In addition, IFN-γ inhibited the expressions of Rab Pases to suppress the mature and transport of melanosomes. IL-18 could rapidly induce Akt and PTEN phosphorylation and p65 expression in B16F10 cells. When treatment with IL-18 and IFN-γ together, the phosphorylation level of Protein Kinase B (Akt) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and expression of p65 NF-κB were inhibited, compared with treated with IL-18 only. Our studies indicated that IFN-γ could directly induce B16F10 cells apoptosis in vitro. Furthermore, we demonstrated that IFN-γ markedly up-regulated IL-18 binding protein (BP) production in normal human foreskin-derived epidermal keratinocytes in dose-dependent manner. UVB irradiation induced protease-activated receptor-2 (PAR-2) expression in NHEK, IFN-γ could inhibit this enhancement in a dose-dependent manner. These data suggest that IFN-γ plays a role in regulating inflammation- or UV-induced pigmentary changes, in direct/indirect manner.

Solid-State E-to-Z Photoisomerization of 4-Dimethylaminoazobenzene Examined by Higher-Order Derivative Spectra

Abstract E-to-Z photoisomerization of 4-dimethylaminoazo-benzene (DMAz) in solution and in aqueous dispersion of fine crystals was analyzed by means of higher-order derivatives. UV-induced changes in derivative spectra of DMAz in hexane led to the identification of vibration level transitions (VLTs) of both E- and Z-isomers and to the estimation of conversions of photoisomerization by tracing extrema of VLT sub-peaks of E-isomer. An aqueous dispersion of DMAz crystals prepared by bead-milling exhibits an extraordinarily broad n,π*-band, which is quite different from that in solution. The irradiation of the dispersion with 365 nm light resulted in the decrement of the absorption band due to the solid-state photoisomerization. The corresponding eighth-derivatives showed the distinctive decline of VLT bands assignable to E-isomer to confirm the photoisomerization. The UV-induced decrement of VLT bands was followed by plotting extremum values of the eighth-order derivatives as a function of exposure time. It was proposed that the solid-state photoisomerization of DMAz is comprised of the fast process at the surface layers and the subsequent slow one in the bulk, taking the observation into account that the melting depression of melting transition occurs by the nanodownsizing of the crystals.

One-Reactant Photografting of ATRP Initiators for Surface-Initiated Polymerization.

Self-initiated photografting polymerization is used to couple the polymerizable initiator monomer 2-(2-chloropropanoyloxy)ethyl acrylate to a range of polymeric substrates. The technique requires only UV light to couple the initiator to surfaces. The initiator surface density can be varied by inclusion of a diluent monomer or via selection of initiator and irradiation parameters. The functionality of the initiator surface is demonstrated by subsequent surface-initiated atom transfer radical polymerization. Surfaces are characterized by x-ray photoelectron spectroscopy (XPS), ellipsometry, and atomic force microscopy (AFM), and UV-induced changes to the initiator are assessed by (1) H NMR and gel permeation chromatography (GPC). This is the first time this one-reactant one-step technique has been demonstrated for creating an initiator surface of variable density.

Incipient UV-Induced Structural Changes in Neutrophil Granulocytes: Morphometric and Texture Analysis of Two-Dimensional Digital Images.

The aim of this study is to determine the ability and consequent significance of fractal and lacunarity analysis together with computational morphometric and gray-level co-occurrence matrix (GLCM) analysis in detecting subtle initial UVB-induced chromatin and cytosolic changes in neutrophil granulocytes. In addition, the direction and potential significance of the observed changes is speculated. Feulgen-stained neutrophils are pictured and their digitalized images are analyzed in specialized software for digital image processing and ImageJ analysis. Significant statistical difference is observed (p0.05). For other parameters there was mostly high statistical significance (p>0.05). Significant unmatched correlations were found as sensitive markers of early morphological changes in cells exposed to UV light. In addition, the correlation between nuclear area and entropy was determined and was highly significant (p<0.001). UVB light, due to its high absorbance by DNA molecules, leads to double behavior of the cells. On one hand, cells start to rearrange but on the other UV light starts very early to immediately damage the cell. All these processes are very subtle in their intensity and GLCM analysis and computational imaging methods based on fractal geometry, i.e. fractal and morphometric analysis, in particular their combination, are very sensitive for detecting and describing these early chromatin changes.

Changes in Cell Adhesiveness and Physicochemical Properties of Cross-Linked Albumin Films after Ultraviolet Irradiation.

We discovered the unique cell adhesive properties of ultraviolet (UV)-irradiated albumin films. Albumin films prepared using a cross-linking reagent with epoxy groups maintained native albumin properties, such as resistance to cell adhesion. Interestingly, the cell adhesive properties of films varied depending upon the UV irradiation time; specifically, cell adhesiveness increased until 2 h of UV irradiation, when the cell number attached to the film was similar to that of culture dishes, and then cell adhesiveness decreased until 20 h of UV irradiation, after which the surface returned to the initial non-adhesive state. To elucidate the molecular mechanisms underlying this phenomenon, we examined the effect of UV irradiation on albumin film properties. The following changes occurred in response to UV irradiation: decreased α-helical structure, cleavage of albumin peptide bonds, and increased hydrophilicity and oxygen content of the albumin film surface. In addition, we found a positive correlation between the degree of cell adhesion and the amount of fibronectin adsorbed on the film. Taken together, UV-induced changes in films highly affect the amount of cell adhesion proteins adsorbed on the films depending upon the irradiation time, which determines cell adhesion behavior.

The cross-talk between electrophiles, antioxidant defence and the endocannabinoid system in fibroblasts and keratinocytes after UVA and UVB irradiation

BackgroundUV, including UVA and UVB radiation, is one of the most ubiquitous environmental stress factors to human skin and leads to redox imbalance and, consequently, photoaging and cancer development. The aim of the study was to verify which skin cells, keratinocytes or fibroblasts, were more susceptible to UVA or UVB irradiation. ObjectiveKeratinocytes and fibroblasts were subjected to UVA and UVB irradiation. MethodsThe redox potential (superoxide anion generation and antioxidant level/activity), electrophile level and endocannabinoid system were estimated. ResultsThe results presented in this paper demonstrate a strong relationship between UV-induced oxidative stress and changes in the endocannabinoid system. Simultaneously, in irradiated cells, the transcription factors Nrf1, Nrf2 and NFκB are activated to varying degrees. Fibroblasts have a greater susceptibility to ROS generation and transcription factor activation after both UVA and UVB irradiation than keratinocytes. Keratinocytes are more sensitive to changes in the electrophile levels connected with oxidative stress compared to fibroblasts. ConclusionThe differences demonstrated in the response of the tested cells to UV irradiation allow for a better understanding of the mechanisms occurring in the human skin, which may be exploited for future therapies in dermatology.

Inhibition of UV-induced matrix metabolism by a myristoyl tetrapeptide.

Regulation of extracellular matrix (ECM) composition is important in tissue homeostasis and function. We screened small peptides for their ability to inhibit ultraviolet (UV)-induced cell metabolism in epidermal fibroblasts. We found that UV irradiation increased matrix metalloproteinase (MMP) expression and inflammatory gene expression in human Hs68 fibroblast cells. We also demonstrated that a myristoyl tetrapeptide with the amino acid sequence Gly-Leu-Phe-Trp (mGLFW) suppressed the UV-induced expression of MMPs and inflammatory genes. Moreover, mGLFW stimulated the expression of ECM proteins in Hs68 fibroblasts. In order to provide the mechanism of action for mGLFW, we investigated UV-induced signaling changes in the presence of mGLFW using a cDNA microarray. UV exposure increased the expression of MMP genes, such as MMP1, MMP3, and MMP14, and inflammation-related genes, including interleukin 1 receptor and peroxisome proliferator-activated receptor gamma (PPARγ). Treatment with mGLFW abrogated the UV-induced expression of MMP-related genes and inflammatory genes. In addition, mGLFW increased the expression of collagen genes, including COL1A1, COL1A2, and COL5A1. We examined whether the activation of AP-1, a UV-activated transcription factor, is suppressed by mGLFW. The results demonstrated that AP-1 expression increased upon UV exposure and that this expression was inhibited by mGLFW. In conclusion, our results demonstrate that mGLFW reversed the effects of UV exposure by enhancing the expression of collagen proteins and suppressing the expression of MMPs, which degrade the ECM.

Plantago asiatica extracts prevent skin photoaging in hairless mice

In this study, we examined the anti-wrinkle effects of Plantago asiatica seed (PAS) on UV-induced human dermal fibroblasts (HDFs) and hairless mice models to determine if an anti-inflammatory agent could also be developed as an anti-aging treatment. Acute UV irradiation induced matrix metallproteinase (MMP)-1 protein expression levels, but this was suppressed by PAS in HDFs. Next, we investigated the effect of PAS on UV-induced skin changes in hairless mice. Chronic UV exposure of the dorsal skin increased skin thickness and induced wrinkle formation. PAS significantly suppressed UV-induced morphologic skin changes. In addition, MMP-1 expression was dramatically attenuated by treatment with plantainoside D which was purely isolated from PAS, indicating that this is the principle compound inhibiting MMP-1 expression in HDFs. Taken together, our data suggest that PAS can prevent the harmful effects of UV that lead to skin aging.

UV-induced retinal proteome changes in the rat model of age-related macular degeneration

Age-related macular degeneration (AMD) is characterized by irreversible damage of photoreceptors in the central posterior part of the retina, called the macula and is the most common cause of vision loss in those aged over 50. A growing body of evidence shows that cumulative long-term exposure to UV radiation may be harmful to the retina and possibly leads to AMD irrespective of age. In spite of many research efforts, cellular and molecular mechanisms leading to UV-induced retinal damage and possibly retinal diseases such as AMD are not completely understood. In the present study we explored damage mechanisms accounting for UV-induced retinal phototoxicity in the rats exposed to UVA and UVB irradiation using a proteomics approach. Our study showed that UV irradiation induces profound changes in the retinal proteomes of the rats associated with the disruption of energy homeostasis, oxidative stress, DNA damage response and structural and functional impairments of the interphotoreceptor matrix components and their cell surface receptors such as galectins. Two small leucine-rich proteoglycans, biglycan and lumican, were identified as phototoxicity biomarkers associated with UV-induced disruption of interphotoreceptor matrix (IPM). In addition, UVB induced activation of Src kinase, which could account for cytoskeletal rearrangements in the retina was observed at the proteomics level. Pharmacological intervention either to target Src kinase with the aim of preventing cytoskeletal rearrangements in the retinal pigment epithelium (RPE) and neuronal retina or to help rebuild damaged IPM may provide fresh avenues of treatment for patients suffering from AMD.

UV exposure modulates hemidesmosome plasticity, contributing to long-term pigmentation in human skin.

Human skin colour, ie pigmentation, differs widely among individuals, as do their responses to various types of ultraviolet radiation (UV) and their risks of skin cancer. In some individuals, UV-induced pigmentation persists for months to years in a phenomenon termed long-lasting pigmentation (LLP). It is unclear whether LLP is an indicator of potential risk for skin cancer. LLP seems to have similar features to other forms of hyperpigmentation, eg solar lentigines or age spots, which are clinical markers of photodamage and risk factors for precancerous lesions. To investigate what UV-induced molecular changes may persist in individuals with LLP, clinical specimens from non-sunburn-inducing repeated UV exposures (UVA, UVB or UVA + UVB) at 4 months post-exposure (short-term LLP) were evaluated by microarray analysis and dataset mining. Validated targets were further evaluated in clinical specimens from six healthy individuals (three LLP+ and three LLP-) followed for more than 9 months (long-term LLP) who initially received a single sunburn-inducing UVA + UVB exposure. The results support a UV-induced hyperpigmentation model in which basal keratinocytes have an impaired ability to remove melanin that leads to a compensatory mechanism by neighbouring keratinocytes with increased proliferative capacity to maintain skin homeostasis. The attenuated expression of SOX7 and other hemidesmosomal components (integrin α6β4 and plectin) leads to increased melanosome uptake by keratinocytes and points to a spatial regulation within the epidermis. The reduced density of hemidesmosomes provides supporting evidence for plasticity at the epidermal-dermal junction. Altered hemidesmosome plasticity, and the sustained nature of LLP, may be mediated by the role of SOX7 in basal keratinocytes. The long-term sustained subtle changes detected are modest, but sufficient to create dramatic visual differences in skin colour. These results suggest that the hyperpigmentation phenomenon leading to increased interdigitation develops in order to maintain normal skin homeostasis in individuals with LLP.