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Hyperpigmented spots develop earlier and with a higher incidence in Asian individuals compared with Europeans. Although actinic lentigines (AL) are very common, the biological events underlying their formation remain ill-defined.
Objective
AL from Japanese volunteers were characterized through morphological and gene expression analyses. Data were then compared with published data on European volunteers.
Methods
AL on hands were selected through dermoscopic imaging and pattern scoring in Japanese women. Skin biopsies of AL and adjacent non-lesional (NL) skin were processed for histology and gene expression profiling. Japanese and European studies were compared after harmonizing the data using the same mathematical and statistical methods.
Results
Histologically, AL from Japanese individuals revealed deep epidermal invaginations with melanin accumulation in the depth of epidermal rete ridges. Transcriptomic data identified 245 genes differentially expressed in AL versus NL skin samples, associated with the different skin compartments and multiple functional families and biological processes, such as epidermal homeostasis, extracellular matrix organization and ion binding/transmembrane transport. Strikingly, melanogenesis-related genes were not significantly modulated in AL compared with NL skin.
Comparison of the molecular profiles of Japanese and European AL showed that a huge majority of genes were modulated in the same way, recapitulating the overall biological alterations.
Conclusion
AL from Japanese volunteers exhibited morphological and molecular alterations of the whole skin structure with impairment of multiple biological functions similar to that found in European women. These findings will contribute to the development of efficient treatments of AL lesions.
Actinic lentigines (AL) are very common hyperpigmented lesions. They develop on chronically sun-exposed skin usually after 35–40 years of age and represent a visible sign of skin ageing [
]. The presence of more or less pronounced elongated rete ridges is a histological hallmark of AL. They can take the form of characteristic club-shaped extensions into the dermis [
]. Although very common, the biological mechanisms underlying AL formation remain unclear. The modulation of several molecular pathways has been reported in AL, such as KGF/KGFR [
] suggested that the molecular alterations in AL seem to be related to the lesion grade and to evolve through its progression.
In a previous study, AL from European women displaying an elongated dermoscopy pattern were selected as advanced lesions. Increased melanin content and drastic disorganization of the whole cutaneous structure confirmed the grade of the selected lesions [
]. Transcriptomic analysis of lesional skin versus non-lesional skin revealed that most of the functional alterations were not related to melanogenesis but rather to various biological functions, such as epidermal homeostasis, inflammation, ion channels and transport and interestingly to the modulation of genes linked to extracellular matrix (ECM) and DEJ. Local modifications of the dermal structure were confirmed at the protein level especially in the sub-epidermal zone [
AL lesions are observed in all skin colour types, but the onset, frequency or severity highly depends on the studied population, especially with respect to constitutive pigmentation and ancestry [
]. These differences cannot only be related to the constitutive pigmentation since Asian populations from Northern East Asian countries, such as Japan and China, correspond to Light and Intermediate groups (ITA° skin colour classification), close to the European population [
]. Search for genetic predisposition for lentigines in Japanese and German cohorts revealed that 12 among 25 single-nucleotide polymorphisms (SNPs) relevant to melanin synthesis were differentially distributed between the 2 populations but only 1 variant of SLC24A5 gene significantly correlated with the occurrence of lentigines [
For Asian population, there is a high demand for an effective AL treatment explaining the increasing practice of aesthetic procedures, especially laser treatments. The risk of developing post-inflammatory hyperpigmentation (PIH) after such invasive treatments, however, is high (20–30%) [
Comparative study of treatment efficacy and the incidence of post-inflammatory hyperpigmentation with different degrees of irradiation using two different quality-switched lasers for removing solar lentigines on Asian skin.
J. Eur. Acad. Dermatol. Venereol.: JEADV.2013; 27: 307-312
]. Therefore, a better understanding of the physiopathological features of AL in Asian individuals is needed to propose effective and safe topical treatments.
To identify the potential specific features of AL lesions in Asian compared with European individuals, a study was conducted in Japanese women. A homogeneous group of advanced AL lesions was selected using epiluminescence imaging and pigmented pattern scoring, as previously described [
]. Morphological analysis and gene expression profiling were performed on AL compared with adjacent non-lesional (NL) skin. Results were then compared to previous data obtained from AL lesions of European volunteers.
2. Material and methods
2.1 Japanese study design
A single-centre, open, randomised prospective clinical study was performed with 20 Japanese women, aged 54–71, phototype III-IV. Volunteers provided written informed consent. The protocol complied with the Helsinki declaration and was approved by the local ethics committee (Study N°503 approved by Nagoya City University of Medicine).
2.1.1 AL selection
AL from the dorsal side of the hands were selected through dermoscopic imaging (X70 magnification, Fotofinder dermoscope®, Teachscreen, Germany) and pigmented pattern scoring using the previously described methodology and selection criteria [
Pairs of 3-mm biopsies (AL lesion and adjacent NL skin) were obtained from each volunteer. One set of biopsies (8 volunteers) was processed for histology, Fontana-Masson staining and microphthalmia transcription factor (MITF) immunostaining. The other set (12 volunteers) was used for gene expression profiling using Affymetrix® U133A 2.0 chips (Affymetrix, USA).
2.1.3 Bioinformatics and statistical analysis
Raw data was normalized using the Robust Multichip Average method. Unsupervised analysis and clustering were performed using a Non-negative Matrix factorization (NMF) approach, and a supervised differential analysis was performed using a T-test for non-paired data. After fold-change and P-value cut-offs were applied (mean fold change between AL and NL ≥ 1.5 for up-regulated genes or ≤ −1.5 for down-regulated genes, adjusted P-value<0.05), results from both approaches were pooled. Raw expression data have been deposited in NCBI's Gene Expression Omnibus (GEO) database (accession number GSE192565).
2.2 European study
Fifteen European women aged 51–67 years, phototype II-III were included after providing written informed consent. The protocol complied with the Helsinki declaration and was approved by the local ethics committee (Comité de Protection des Personnes Sud Méditerranée V, ID 2007-A00175–48). Selection of AL lesions and processing of AL and NL biopsies for transcriptomic analysis are detailed in Warrick et al. [
]. Transcriptomic raw data were re-analysed using the same software and methodology as described in this paper, to make the comparison relevant. Raw expression data have been deposited in NCBI's Gene Expression Omnibus (GEO) database (accession number GSE192564).
Details concerning skin biopsies, morphometric analysis, immunostainings, microarrays processing, bioinformatics and statistical analysis are provided in Appendix A (Supplementary Materials and Methods).
3. Results and discussion
3.1 Morphological analysis of AL from Japanese volunteers
Histological analysis was performed on AL selected with defined dermoscopic criteria using dedicated software (area occupied by elongated patterns over 20%, see Materials and Methods and Appendix A). Compared with adjacent NL skin, AL sections showed a drastic deformation of the DEJ with deeply clubbed and budding epidermal invaginations into the dermis (Fig. 1a). The undulation index was significantly higher in AL versus NL samples confirming the high degree of DEJ deformation in AL (Fig. 1b). Dermoscopic pictures, scoring and histological illustrations for all volunteers are presented in Appendix B, Fig. B.1. Increased melanin accumulation was observed and quantified in the epidermis of AL, particularly along the basal layer and deep in epidermal rete ridges (Fig. 1c-d). MITF-immunostaining showed a correct distribution of melanocytes in the basal layer and the absence of clusters in AL and NL sections (Fig. 1e). Although the number of melanocytes per unit length of the stratum corneum was increased in AL compared with NL skin, the number of melanocytes per unit of basal layer length was constant, confirming a physiological distribution of melanocytes along the DEJ in AL (Fig. 1f). These drastic morphological alterations in AL have been associated with later stage lesions [
], the severe alterations with profound DEJ deformation observed in all Japanese lesions confirmed a correlation between the score of elongated dermoscopic pattern and later stage–associated histological defects. These observations strengthen (i) the robustness of the methodology to select homogenous AL lesions and (ii) the presence of similar alterations independently of the geographical origin.
Fig. 1Morphological analysis of actinic lentigines (AL) and adjacent non-lesional skin (NL) of Japanese volunteers. (a) Representative histological features (HES staining) of NL and AL for 2 subjects (J4, J8) show the prominent deformation of the dermal epidermal junction and the presence of epidermal invaginations into the superficial dermis. (b) The undulation index (ratio between the length of the basal layer and the length of the stratum corneum) measured on 10 HES-stained sections per biopsy for each subject (n = 8) was significantly higher in AL versus control NL skin. (c) Fontana-Masson staining of AL and NL skin from the same 2 subjects illustrates the accumulation of melanin in the basal layer of the epidermis. (d) Quantification of the melanin content by image analysis in 10 FM-stained sections per biopsy for each subject (n = 8) indicates significantly increased basal melanin levels in AL versus NL. (e) Representative immunostaining of microphtalmia transcription factor (MITF) of NL and AL for the same 2 subjects show a regular positioning of melanocytes (red) along the basal layer. (f) Quantification of MITF-positive cells on sections from AL and NL (8 subjects). An increase in the number of melanocytes per unit of stratum corneum (SC) length is observed but no significant modulation of the number of melanocytes per unit of length of basal layer. This shows even distribution of melanocytes along the epidermal basal layer. The P-value is indicated when a statistical difference is observed between AL and NL groups using Wilcoxon signed rank test (P < 0,05). N.s. non-significant. (a), (c), (e): magnification X200.
] displayed a good separation between Japanese AL and NL biopsies (P-value<10–4), thus confirming the specific molecular signature of AL (Appendix B, Fig. B.2). After application of a fold-change (FC) cut-off and the addition of probesets found differentially modulated in a complementary supervised analysis (see Appendix A), 332 probesets were found differentially expressed in AL compared with NL skin, corresponding to 245 genes, 119 upregulated (mean FC ≥ 1,5) and 126 downregulated (mean FC ≤ −1,5).
A gene ontology study was performed using GOTM (http://bioinfo.vanderbilt.edu/gotm/) on the 332 probesets (Appendix C, Table C.1). The main biological functions were related to development and morphogenesis and linked to epidermal biology. The main cellular component corresponded to “extracellular region”, specifically ECM and basement membrane.
Genes were classified into functional families using a targeted bibliographic analysis focused on skin biology (Fig. 2). The main represented functions were linked to Development & Morphogenesis, Epidermis, Extracellular matrix & DEJ, Transmembrane transport & Channels, Inflammation & immunity, Intercellular transport & Cytoskeleton and Metabolism.
Fig. 2Functional families associated with the 245 genes differentiating AL from NL skin in Japanese volunteers. Biological functions associated with the 119 upregulated genes (a), and the 126 downregulated genes (b) in AL versus NL skin are shown. The number of genes related to the total number of modulated genes (%) in each family is indicated.
Global gene expression analysis thus revealed a clear molecular signature differentiating AL from NL skin. The diversity of GO terms and functional families is consistent with the overall disorganization of the cutaneous structure in AL.
3.3 Analysis of pigmentation-related genes in AL from Japanese volunteers
Because AL are hyperpigmented disorders, a specific analysis was performed for pigmentation-related genes. Strikingly, none was significantly modulated in AL compared with NL skin (Appendix C, Table C.2). This result is in line with our previous report [
]. This suggests that melanocyte alterations cannot be considered mandatory in AL, but it cannot exclude the stimulation of melanogenesis earlier in lesion development. A slight overexpression of the KITLG gene was observed. KITLG/SCF, the major ligand for c-KIT receptor, is implicated in the regulation of pigmentation [
]. Besides, the slight downregulation of pro-opiomelanocortin (POMC) gene, the precursor of the propigmenting α-melanocyte-stimulating hormone (α-MSH) [
], a comparative analysis of gene expression profiles was performed. In the time interval between the 2 studies, methods and software were upgraded and became more robust, allowing for better discrimination of genes differentially expressed in AL and NL conditions. Therefore, a rigorous comparison required a re-analysis of European data using the same statistical methods as used for the Japanese study (see Appendix A). A list of 266 probesets corresponding to 196 genes differentially expressed in AL versus NL condition was thus established for the European study. Eighty per cent of the probesets in the new list were included in the first analysis and recapitulated all the functional dysregulations previously described [
3.5 Common Japanese and European AL molecular signature
Comparison of probesets with a P-value< 0.05 in at least 1 study showed that more than 90% of the probesets were modulated in the same way in European and Japanese AL (Fig. 3a). Comparison revealed that 178 probesets, corresponding to 136 genes, were significantly modulated in the same way in AL in both studies with an absolute mean FC ≥ 1.5, representing a strong signature of AL lesions, regardless of the population studied.
Fig. 3Comparison of gene expression profiles and functional families in AL versus NL skin in Japanese and European studies. (a) Comparison of lists of probesets with a P-value< 0.05 in at least 1 study using TIBCO Spotfire (TIBCO Software, Palo Alto, USA). Fold-change values in the European study and in the Japanese study are represented on the vertical and horizontal axes, respectively. This global comparison shows that more than 90% of all probesets were modulated in the same way in European and Japanese AL. FC Eu: Fold-change European study; FC Jp: Fold-change Japanese study. Green: common probesets significantly modulated in both studies with mean FC value ≥ 1,5 (for up-regulated genes) or ≤ −1,5 (for down regulated genes) and an adjusted P-value< 0.05; Blue: probesets significantly modulated in the European study only; Red: probesets significantly modulated in the Japanese study only. ns: not significantly modulated. (b) Comparison of biological functions associated with genes differentiating AL from NL skin in European (n = 196) and Japanese (n = 245) volunteers with the biological functions associated with common genes, modulated in both studies (n = 245). Note that the same functional families are similarly represented in European and Japanese AL, and that the common signature recapitulates this biological profile.
Because most other probesets were also modulated in the same way in both populations, probesets with an absolute mean FC ≥ 1.5 in one study and between 1.25 and 1,5 in the other (P-value<0.05) were also added to the common AL signature leading to a list of 245 common genes. Only 15 and 22 genes could then be considered as being specifically modulated in AL from European and Japanese volunteers, respectively.
The common genes differentially expressed in both studies were distributed in functional families, and no specific unexpected function was highlighted, reproducing the signature already found in the 2 separate studies (Fig. 3b and Appendix B, Fig. B.3).
We then focused the analysis on substantial functions, namely those related to “Development & morphogenesis/ Epidermis proliferation/differentiation”, “Transmembrane transport & Channels” and “Extracellular matrix & DEJ” (Table 1).
Table 1Genes associated with development and morphogenesis, epidermal proliferation and differentiation, transmembrane transport and ion channels, extracellular matrix and dermal epidermal junction (DEJ), found to be significantly modulated in AL versus NL skin. Common genes from Japanese and European studies are represented here. FC: fold-change.
Function
Gene symbol
Name
FC Japan
FC Europe
Development &
PITX2
paired-like homeodomain 2
5,4
4,42
Morphogenesis
HOXD11
homeobox D11
5,06
3,61
ZIC2
Zic family member 2 (odd-paired homolog. Drosophila)
4,61
5,13
HOXD10
homeobox D10
3,92
3,67
HOXB7
homeobox B7
3,13
2,41
HOXD8
homeobox D8
2,97
2,44
PAX6
paired box 6
2,67
2,09
DLX1
distal-less homeobox 1
2,52
2,29
DLX2
distal-less homeobox 2
2,16
1,91
FOXF2
forkhead box F2
1,92
1,69
PLAG1
pleiomorphic adenoma gene 1
1,91
2,01
WNT3
wingless-type MMTV integration site family, member 3
1,78
1,4
ODZ2
odz, odd Oz/ten-m homolog 2 (Drosophila)
1,7
1,28
FOXP2
forkhead box P2
1,62
1,54
ASCL2
achaete-scute complex homolog 2 (Drosophila)
1,62
1,4
SOX6
SRY (sex determining region Y)-box 6
1,55
1,54
EN2
engrailed homeobox 2
1,53
1,7
RSPO3
R-spondin 3 homolog (Xenopus laevis)
1,48
1,6
PITX1
paired-like homeodomain 1
1,34
1,54
NHLH2
nescient helix loop helix 2
1,32
1,57
CITED2
Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2
Modulations of representative genes from each functional family were validated using quantitative PCR analysis (qPCR) (Appendix A Supplementary Material and Methods, Appendix C Table C.3). For each volunteer, a strong correlation was found between qPCR and microarray results. Moreover, the clear consistency of results in both Japan and Europe studies confirmed the robustness of the clinical criteria used to select a homogeneous set of AL lesions.
3.6 Genes associated with development & morphogenesis/ epidermis proliferation/differentiation modulated in Japanese and European AL
The genes involved in development and morphogenesis and significantly modulated in AL in both studies are listed in Table 1. They may be related to complete disorganization of the global cutaneous structure observed in AL, in line with a new gene expression program driven by transcription factors involved in morphogenesis and tissue patterning such as Hox family members [
] were upregulated. When expressed in adult cells those genes are thought to ensure a maintenance of the normal phenotype. Due to their role as master transcriptional regulators, modulation in their expression may be associated with phenotypic changes as shown in various cancers during oncogenic transformation. Unfortunately, the cutaneous function of the HOX genes modulated in this study is not known, except for HOXB7 which is implicated in squamous cell carcinoma invasion [
Specific knockdown of HOXB7 inhibits cutaneous squamous cell carcinoma cell migration and invasion while inducing apoptosis via the Wnt/beta-catenin signaling pathway.
Am. J. Physiol. Cell Physiol.2018; 315 (C675-c686)
In parallel, genes related to epidermal proliferation and differentiation were also identified as strong molecular markers of AL (Table 1). Among them, KRT15 and CCDN2, biomarkers for the epidermal proliferative basal layer [
Cyclin D2 overexpression in transgenic mice induces thymic and epidermal hyperplasia whereas cyclin D3 expression results only in epidermal hyperplasia.
]. Immunostaining analysis confirmed the increase of K15 protein in the basal layer of AL versus NL skin, particularly impressive in epidermal invaginations (Fig. 4). These data suggest that basal keratinocytes with increased proliferative activity contribute to the development of epidermal rete ridges formation. In contrast genes that participate in the terminal differentiation process and cornified envelope formation, such as cornulin [
], were down regulated. Simultaneous alterations in both epidermal proliferation and differentiation reinforce the fact that epidermal homeostasis is globally compromised in AL.
Fig. 4Immunostaining of K15 protein in sections of AL and NL skin. Representative illustrations of lesions (AL) and adjacent non-lesional skin (NL) for 2 subjects from (a) the European study (E3, E15), and (b) the Japanese study (J1, J3) show the increased staining of K15 protein in the basal layer of AL versus NL, notably remarkable in epidermal invaginations (bar = 100 µm).
3.7 Genes involved in transmembrane transport & channels modulated in Japanese and European AL
Strikingly, almost 30 genes coding for transmembrane transporters and ion channels were differentially expressed in AL versus NL, preferentially down-regulated (Table 1). Their function in skin is mainly not described, although some genes, such as ABCG2, CHRNA9 or SLC1A3 may be related to epidermal homeostasis. The transporter ABCG2 is overexpressed in the basal layer of healing skin [
] can be linked to other markers of proliferation in AL. Cholinergic receptor α9 (CHRNA9 gene) is involved in the adhesion and motility of keratinocytes at early stages of epidermal morphogenesis [
]. The glutamate transporter SLC1A3 may also have a role in keratinocyte differentiation orchestration, based on the essential role of glutamate in the barrier function and re-epithelialization process [
Additionally, the downregulation of several genes associated with calcium flux (CACNA2D1, ATP13A4, SLC8A1, TMEM20/SLC35G1) strengthens the hypothesis of impaired epidermal differentiation and skin barrier given that the gradient of epidermal calcium concentration is essential in these processes [
] in addition to other critical functions such as cell proliferation and oxidative stress defence.
Modulation of these genes and other SLC transporter genes (SCL39A14, SLC6A14, SLC16A14, SLC45A4, SCL46A2) with ill-defined functions may reflect a global perturbation of cell activity and interaction with their microenvironment, in connection with the diversity of functional families and processes altered in AL.
3.8 Extracellular matrix (ECM) and DEJ-related genes modulated in Japanese and European AL
Table 1 shows genes coding for DEJ and ECM components, and TGFβ/BMP pathways regulation [
Over-expression of basement membrane genes in AL such as FRAS1 and THBS2 may be consistent with the increased length of the DEJ and with the formation of elongated epidermal rete ridges. These drastic structural modifications strongly suggest a reorganization of the DEJ and dermis during AL formation, in line with modifications of the ECM (collagens, proteoglycans) and DEJ related genes but also with genes highly involved in matrix remodeling, such as PLAU, ADAMTLS3, PI3 (elafin) or lysozyme (LYZ). Of particular interest, the two latter genes are associated with dermal photoaging and solar elastosis [
]. Interestingly, dermal photoaging is of growing interest with regard to the physiopathology of pigmentary disorders, as recently highlighted for the melasma [
Finally, the common signature of AL from Japanese and European subjects recapitulates the major functions observed separately. In the present study, however, only a small number of modulated genes represent a specific signature for each geographical origin of volunteers.
3.9 Genes significantly modulated in AL versus NL in only one population
Only 22 genes were specifically modulated in AL versus NL skin in Japanese volunteers but not in European ones (Table 2). These genes belong to most of the functional families already described, indicating that lesions of Japanese volunteers are not associated with particular biological functions. In addition, the number of modulated genes in the different functional families is low (between 1 and 4 genes) except for Epidermis/proliferation and differentiation function where 6 genes were specifically modulated in Japanese AL. Four genes belong to the EDC (epidermal differentiation complex), a specific chromosomic locus that contains genes such as SPRR or LCE which code for actors of epidermal terminal differentiation [
]. Interestingly SPRR2G even showed a trend to be inversely modulated in lesions from Japanese volunteers compared to European ones. Studies aiming at comparing skin barrier function depending on ethnic origin are often inconclusive and did not evidence clear differences [
]. The clinical relevance of this finding thus remains to be further investigated.
Table 2Genes significantly modulated in AL versus NL skin in a specific group of volunteers. FC: fold-change. Numbers in bold indicate that the gene is significantly modulated in AL versus NL skin (absolute FC ≥ 1.5 and P-value<0.05).
Function
Gene Symbol
Name
FC Europe
FC Japan
Genes significantly modulated in AL versus NL skin in Japanese but not European volunteers
Epidermis
SPRR2B
small proline-rich protein 2B
1,32
2,37
KRT33A
keratin 33A
1,55
1,77
SPRR3
small proline-rich protein 3
1,19
1,73
SPRR2G
small proline-rich protein 2 G
-1,24
1,58
LCE3D
late cornified envelope 3D
1,10
1,55
KRT6A
keratin 6A
1,43
1,52
Innate immunity
CD1B
CD1b molecule
1,05
1,63
C1S
complement component 1, s subcomponent
1,21
1,51
//SERPINB3//SERPINB4//
serpin peptidase inhibitor, clade B (ovalbumin), member 3//member 4
1,29
1,51
Inflammation
CCL13
chemokine (C-C motif) ligand 13
1,31
1,65
LCN2
lipocalin 2
1,35
1,57
Extracellular matrix
COMP
cartilage oligomeric matrix protein
1,40
2,04
FREM2
FRAS1 related extracellular matrix protein 2
1,29
1,83
Intercellular communication
IGFBP6
insulin-like growth factor binding protein 6
1,43
1,55
SCUBE2
signal peptide, CUB domain, EGF-like 2
1,20
1,52
Oxidative stress
GSTA3
glutathione S-transferase alpha 3
-1,04
-1,51
Intracellular communication
GPR98
G protein-coupled receptor 98
1,07
1,92
Development
OSR2
odd-skipped related 2 (Drosophila)
1,42
1,57
Cytoskeleton
NEXN
nexilin (F actin binding protein)
1,39
1,65
Neurons
OMG
Oligodendrocyte myelin glycoprotein
1,35
2,17
Unknown or uncertain
C9orf152
chromosome 9 open reading frame 152
-1,01
-1,56
//GABBR1//UBD//
gamma-aminobutyric acid (GABA) B receptor, 1 // ubiquitin D
1,22
1,61
Genes significantly modulated in AL versus NL skin in European but not Japanese volunteers
Intercellular communication
SCGB1D2
secretoglobin, family 1D, member 2
1,66
1,01
HTR3A
5-hydroxytryptamine (serotonin) receptor 3A
-1,54
-1,07
Epidermis
SFRP4
secreted frizzled-related protein 4
1,74
1,31
EREG
epiregulin
-1,51
-1,20
Ion channels
SLC6A2
solute carrier family 6 (neurotransmitter transporter, noradrenalin), member 2
1,59
1,31
SLC13A2
solute carrier family 13 (sodium-dependent dicarboxylate transporter), member 2
1,51
-1,11
Immunity
PTX3
pentraxin 3, long
1,89
1,08
LAMP3
lysosomal-associated membrane protein 3
-1,58
-1,20
Cell cycle
E2F8
E2F transcription factor 8
-1,55
-1,31
Intracellular communication
CHRM3
cholinergic receptor, muscarinic 3
1,64
-1,05
Cytoskeleton
ACTG2
actin, gamma 2, smooth muscle, enteric
1,60
1,06
Extracellular matrix
ADAMTS5
ADAM metallopeptidase with thrombospondin type 1 motif, 5
Among the 15 genes specifically modulated in European but not in Japanese subjects (Table 2), no specific functional family could be identified, due to the low number of genes in each family.
4. Conclusion
Advanced AL lesions carefully selected according to the same clinical criteria in Japanese and European women displayed similar alterations of the whole skin structure, with the presence of elongated, melanin-loaded epidermal rete ridges. They are associated with a common gene expression profile, with genes involved in multiple biological functions and skin compartments that recapitulate the overall biological alterations of AL lesions, regardless of the origin of the subjects. Interestingly genes related to melanocyte biology are not found modulated. These lesions must therefore be considered globally, and not only through the melanocyte prism. Major modulations of genes related to epidermal homeostasis and the dermal compartment indicate dysregulation of keratinocyte proliferation/stemness, defects in terminal differentiation, and dermal matrix organization. These molecular features may explain the morphological features observed in AL. These findings open new doors for the development of effective treatment of AL aimed at restoring global tissue homeostasis.
Funding sources
This study was funded by L’Oréal Research and Innovation.
Conflicts of interest
All authors, except A. Morita, are or were employees of L’Oréal.
Acknowledgements
We are grateful to Dr Sophie Deret for her constant scientific support and expertise regarding the transcriptomic study and biostatistical analysis.
The patients in this manuscript have given written informed consent to publication of their case details.
Comparative study of treatment efficacy and the incidence of post-inflammatory hyperpigmentation with different degrees of irradiation using two different quality-switched lasers for removing solar lentigines on Asian skin.
J. Eur. Acad. Dermatol. Venereol.: JEADV.2013; 27: 307-312
Specific knockdown of HOXB7 inhibits cutaneous squamous cell carcinoma cell migration and invasion while inducing apoptosis via the Wnt/beta-catenin signaling pathway.
Am. J. Physiol. Cell Physiol.2018; 315 (C675-c686)
Cyclin D2 overexpression in transgenic mice induces thymic and epidermal hyperplasia whereas cyclin D3 expression results only in epidermal hyperplasia.
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