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  • Frequency of somatic mutations in head and neck melanoma: A single institution experience
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2020-01-16
    Emi Dika; Martina Lambertini; Annalisa Patrizi; Cosimo Misciali; Annalisa Altimari; Michelangelo Fiorentino; Barbara Melotti; Barbara Corti; Mattia Riefolo; Giulia Veronesi

    Cutaneous head and neck melanoma (HNM) is a separate subgroup of cutaneous melanoma that has a worse prognosis than other primary sites. The aim of this article is to examine the status of somatic mutations (BRAF, NRAS, and KIT) of primary lesion in head and neck regions in our institution experience. Mutational status was correlated to the clinicopathological features and the disease progression. We retrospectively analyzed 76 cases of primary HNM diagnosed from January 2005 to June 2017, from the database of the Melanoma Unit, University of Bologna. The study included 19 cases with molecular assays. BRAF mutations in HNM was positive in five patients (26.3%); NRAS p.Q61L was detected in a NM of the scalp, when the other cases were wild type for the investigated gene mutations. Interestingly, we found that HNM BRAF mutations were the most representative in our cases, although BRAF mutations in the Literature are less frequently found in melanomas occurring at sites of chronic sun damage such as the head and neck. The aim of this study is to stimulate future research.

    更新日期:2020-01-17
  • Distinct genomic traits of acral and mucosal melanomas revealed by targeted mutational profiling
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2020-01-16
    Zhengyun Zou; Qiuxiang Ou; Yu Ren; Qing Lv; Lanqun Qin; Lianjun Zhao; Shu Su; Xue Wu; Hua Bao; Ao Wang; Dongqin Zhu; Xiaonan Wang; Yang W. Shao; Baorui Liu

    The incidence of melanoma is rising globally including China. Comparing to Caucasians, the incidence of non‐cutaneous melanomas is significantly higher in Chinese. Herein, we performed genomic profiling of 89 Chinese surgically resected primary melanomas, including acral (n = 54), cutaneous (n = 22), and mucosal (n = 13), by hybrid capture‐based next generation sequencing. We show that mucosal melanomas tended to harbor more pathogenic mutations than other types of melanoma, though the biological significance of this finding remains uncertain. Chromosomal arm‐level alterations including 6q, 9p, and 10p/q loss were highly recurrent in all subtypes, but mucosal melanoma was significantly associated with increased genomic instability. Importantly, 7p gain significantly correlated with unfavorable clinical outcomes in non‐cutaneous melanomas, representing an intriguing prognostic biomarker of those subtypes. Furthermore, focal amplification of 4q12 (KIT, KDR, and PDGFRα) and RAD51 deletion were more abundant in mucosal melanoma, while NOTCH2 amplification was enriched in acral melanoma. Additionally, cutaneous melanomas had higher mutation load than acral melanomas, while mucosal melanomas did not differ from other subtypes in mutation burden. Together, our data revealed important features of acral and mucosal melanomas in Chinese including distinctive driver mutation pattern and increased genomic instability. These findings highlight the possibilities of combination therapies in the clinical management of melanoma.

    更新日期:2020-01-16
  • IMP dehydrogenase rod/ring structures in acral melanomas
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2020-01-13
    Gerson D. Keppeke; Denise Barcelos; Mariana Fernandes; Andréia N. Comodo; Daiane P. Guimarães; Leonardo Cardili; Fernando C. L. Carapeto; Luis E. C. Andrade; Gilles Landman

    Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to assemble into large filamentary structures called rods/rings (RR) or cytoophidium (cellular snakes). RR assembly induces a hyperactive state in IMPDH, usually to supply a high demand for GTP nucleotides, such as in highly proliferative cells. We investigate whether aggressive melanoma tumor cells present IMPDH‐based RR structures. Forty‐five ALM paraffin‐embedded tissue samples and 59 melanocytic nevi were probed with anti‐IMPDH2 antibody. Both the rod‐ and ring‐shaped RR could be observed, with higher frequency in ALM. ROC curve analyzing the proportions of RR‐positive cells in ALM versus nevi yielded a 0.88 AUC. Using the cutoff of 5.5% RR‐positive cells, there was a sensitivity of 80% and specificity of 85% for ALM diagnosis. In ALM, 36 (80%) showed RR frequency above the cutoff, being classified as RR‐positive, compared with only 9 (15%) of the nevi (p < .001). Histopathology showed that 71% of the RR‐positive specimens presented Breslow thickness > 4.0mm, compared with only 29% in the RR‐low/negative (p = .039). We propose that screening for RR structures in biopsy specimens may be a valuable tool helping differentiate ALM from nevi and accessing tumor malignancy.

    更新日期:2020-01-13
  • Pathogenesis of a variant in the 5’ untranslated region of ADAR1 in dyschromatosis symmetrica hereditaria
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2020-01-11
    Mutsumi Suganuma; Michihiro Kono; Masayoshi Yamanaka; Masashi Akiyama

    Dyschromatosis symmetrica hereditaria (DSH) is a pigmentary genodermatosis caused by mutations in ADAR1. In this study, we performed mutation analysis on a family that included typical DSH patients. No mutations were found in any coding regions or exon–intron boundary regions of ADAR1, but a previously unreported non‐coding heterozygous variant, c.‐60A>G, was found in the 5' untranslated region (5'UTR) of ADAR1 in the proband and her mother. The function of 5'UTR in mRNA is not well understood. To understand the pathogenesis of the variant and the function of the 5'UTR of ADAR1, we constructed 2 reporter genes carrying the ADAR1 5'UTR sequence with/without the variant between the PGK promoter and a luciferase coding sequence, and performed luciferase assays, semi‐quantitative PCR analyses and polysomal assays. In human melanocytes, c.‐60A>G induced a 16% reduction in transcription and a 51% reduction in translation. Our results indicate that the 5'UTR c.‐60A>G variant adversely affects the post‐transcriptional step in gene expression, leading to DSH. Detailed functional assays of the 5'UTR of ADAR1 in the present study revealed the gene expression to be not only downregulated, but also upregulated by defects in 5'UTR depending on the locations. The regulation of translation by 5'UTR is very complicated.

    更新日期:2020-01-13
  • Altered expression of nuclear factor of activated T cells, Forkhead Box P3 and immune suppressive genes in regulatory T cells of generalized vitiligo patients
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2020-01-09
    Prashant S. Giri; Mitesh Dwivedi; Naresh C. Laddha; Rasheedunnisa Begum; Ankit H Bharti

    The study was aimed to analyze expression of Nuclear factor of Activated T cells (NFATs), Forkhead Box P3 (FOXP3) and their associated genes (sCTLA4, flCTLA4, IL10, TGFB, IL2, IL4, CD25) in regulatory T cells (Tregs) of 48 generalized vitiligo (GV) patients and 45 unaffected controls. The transcripts of NFATC1 to NFATC4, FOXP3, IL10, flCTLA4 (p < .0001), NFAT5 (p = .0003), sCTLA4 (p = .001) and FOXP3 protein in Tregs and plasma IL‐10 levels were reduced significantly (p < .0001) in GV Tregs compared to controls. The FOXP3 promoter polymorphisms [rs3761548(C > A), rs3761547(A > G), rs2232365(A > G)] revealed significantly decreased FOXP3 protein levels in patients Tregs with susceptible AA, GG and GG genotypes (p < .0001, p = .028, p = .022 respectively). The active vitiligo Tregs showed reduced levels of NFATC3, NFATC4, NFAT5, FOXP3, TGFB, flCTLA4 transcripts (p = .0005, p = .0003, p = .0002, p = .020, p < .0001, p = .006 respectively) and FOXP3 and TGF‐β proteins (p = .0394 & p = .0013) compared to stable vitiligo. Early onset patients (1–20 years) demonstrated decreased IL‐10, sCTLA‐4, flCTLA‐4, TGFB, FOXP3 transcripts and FOXP3 protein as compared to late onset patients (41–60 years) (p = .001, p = .003, p = .009, p = .005, p = .038, p = .0226 respectively). Overall, our results for the first time suggest a likely role of NFATs and FOXP3 together with Treg immune suppressive genes in GV pathogenesis and disease progression, warranting additional investigations.

    更新日期:2020-01-11
  • Leptomeningeal Disease in Melanoma Patients: An update to treatment, challenges, and future directions
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2020-01-08
    Isabella C. Glitza; Keiran S.M. Smalley; Priscilla K. Brastianos; Michael A. Davies; Ian McCutcheon; James K.C. Liu; Kamran A. Ahmed; John A. Arrington; Brittany R. Evernden; Inna Smalley; Zeynep Eroglu; Nikhil Khushalani; Kim Margolin; Harriet Kluger; Michael B. Atkins; Hussein Tawbi; Adrienne Boire; Peter Forsyth

    In February 2018 the Melanoma Research Foundation and the Moffitt Cancer Center hosted the Second Summit on Melanoma Central Nervous System (CNS) Metastases in Tampa, Florida. The meeting included investigators from multiple academic centers and disciplines. A consensus summary of the progress and challenges in melanoma parenchymal brain metastases (MBM) was published.(Eroglu et al., 2019) Here, we will describe the current state of basic, translational, clinical research, and therapeutic management, for melanoma patients with leptomeningeal disease (LMD). We also outline key challenges and barriers to be overcome to make progress in this deadly disease.

    更新日期:2020-01-09
  • Extracellular vesicles released by melanocytes after UVA irradiation promote intercellular signaling via miR21
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2020-01-07
    Petra Wäster; Ida Eriksson; Linda Vainikka; Karin Öllinger

    Skin pigmentation is controlled by complex crosstalk between melanocytes and keratinocytes and is primarily induced by exposure to ultraviolet (UV) irradiation. Several aspects of UVA‐induced signaling remain to be explored. In skin cells, UVA induces plasma membrane damage, which is repaired by lysosomal exocytosis followed by instant shedding of extracellular vesicles (EVs) from the plasma membrane. The released EVs are taken up by neighboring cells. To elucidate the intercellular crosstalk induced by UVA irradiation, EVs were purified from UVA‐exposed melanocytes and added to keratinocytes. Transcriptome analysis of the keratinocytes revealed activation of TGF‐β and IL‐6/STAT3‐signaling pathways and subsequent up‐regulation of microRNA (miR)21. EVs induced phosphorylation of ERK and JNK, reduced protein levels of PDCD4 and PTEN and augment anti‐apoptotic signaling. Consequently, keratinocyte proliferation and migration were stimulated and UV‐induced apoptosis was significantly reduced. Interestingly, melanoma cells and melanoma spheroids also generate increased amounts of EVs with capacity to stimulate proliferation and migration upon UVA. In conclusion, we present a novel intercellular crosstalk mediated by UVA‐induced lysosome‐derived EVs leading to activation of proliferation and anti‐apoptotic signaling via miR21.

    更新日期:2020-01-07
  • Protective role of mouse mast cell tryptase Mcpt6 in melanoma
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2020-01-01
    Mirjana Grujic; Lars Hellman; Ann‐Marie Gustafson; Srinivas Akula; Fabio Rabelo Melo; Gunnar Pejler

    Tryptase‐positive mast cells populate melanomas but it is not known whether tryptase impacts on melanoma progression. Here we addressed this and show that melanoma growth is significantly higher in tryptase‐deficient (Mcpt6‐/‐) versus. wild‐type mice. Histochemical analysis showed that mast cells were frequent in the tumor stroma of both wild‐type and Mcpt6‐/‐ mice, and also revealed their presence within the tumor parenchyma. Confocal microscopy analysis revealed that tryptase was taken up by the tumor cells. Further, tryptase‐positive granules were released from mast cells and were widely distributed within the tumor tissue, suggesting that tryptase could impact on the tumor microenvironment. Indeed, gene expression analysis showed that the absence of Mcpt6 caused decreased expression of numerous genes, including Cxcl9, Tgtp2 and Gbp10, while the expression of 5p‐miR3098 was enhanced. The levels of CXCL9 were lower in serum from Mcpt6‐/‐ versus. wild‐type mice. In further support of a functional impact of tryptase on melanoma, recombinant tryptase (Mcpt6) was taken up by cultured melanoma cells and caused reduced proliferation. Altogether, our results indicate a protective role of mast cell tryptase in melanoma growth.

    更新日期:2020-01-02
  • Mouse models of uveal melanoma: Strengths, weaknesses, and future directions
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-12-27
    Jackson R. Richards; Jae Hyuk Yoo; Donghan Shin; Shannon J. Odelberg

    Uveal melanoma is the most common primary malignancy of the eye, and a number of discoveries in the last decade have led to a more thorough molecular characterization of this cancer. However, the prognosis remains dismal for patients with metastases, and there is an urgent need to identify treatments that are effective for this stage of disease. Animal models are important tools for preclinical studies of uveal melanoma. A variety of models exist, and they have specific advantages, disadvantages, and applications. In this review article, these differences are explored in detail, and ideas for new models that might overcome current challenges are proposed.

    更新日期:2019-12-27
  • Tumor genetic heterogeneity analysis of chronic sun‐damaged melanoma
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-12-23
    Adriana Sanna; Katja Harbst; Iva Johansson; Gustav Christensen; Martin Lauss; Shamik Mitra; Frida Rosengren; Jari Häkkinen; Johan Vallon‐Christersson; Håkan Olsson; Åsa Ingvar; Karolin Isaksson; Christian Ingvar; Kari Nielsen; Göran Jönsson

    Chronic sun‐damaged (CSD) melanoma represents 10%–20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra‐tumor heterogeneity (ITH) in CSDhigh melanoma is still unknown. Ultra‐deep targeted sequencing of 40 cancer‐associated genes was performed in 72 in situ or invasive CMM, including 23 CSDhigh cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in‐transit metastases from one CSDhigh melanoma patient. We found no significant difference in mutation frequency in melanoma‐related genes or in mutational load between in situ and invasive CSDhigh lesions, while this difference was observed in CSDlow lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSDhigh melanomas. Sequencing of multiple specimens from one CSDhigh patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSDhigh and CSDlow melanomas are distinct molecular entities that progress via different genetic routes.

    更新日期:2019-12-25
  • Genomic analysis reveals low tumor mutation burden which may be associated with GNAQ/11 alteration in a series of primary leptomeningeal melanomas
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-12-18
    Shannon Fortin Ensign; Kathryn Bollin; Sherri Z. Millis; Brian R. Hinds; Michael Kosty; Christopher Uchiyama

    Primary central nervous system melanoma is rare and characterized by a variable prognosis, and no current treatment guidelines exist. We describe the clinical course of a 70‐year‐old female patient diagnosed with primary leptomeningeal melanoma (LMN) whose case represents the diagnostic and management challenges of this tumor. Targeted genomic sequencing of 315 genes from this tumor revealed GNAQ Q209L mutation and low (4 mutations/Megabase) tumor mutation burden (TMB). Wild‐type NRAS, KIT, and BRAF were also observed. A cohort of 4,787 melanomas was subsequently analyzed to identify additional primary central nervous system melanomas, of which 10 additional tumors met pathologic criteria (0.21% of total melanoma cohort). These tumors were genomically assessed according to the same targeted sequencing panel, and 6 of the tumors were also found to harbor a GNAQ mutation. All 10 tumors had low (less than or equal to 2 mutations/Megabase) TMB indicating a potential trend between G‐protein‐coupled receptor (GPCR) alterations and low TMB in LMNs. GPCR alterations were found to significantly correlate with TMB across the cohort of 4,787 melanomas, supporting this potential finding in the limited LMN subset.

    更新日期:2019-12-19
  • Fast oxidation of α‐melanocyte stimulating hormone and derived peptides under laboratory conditions causes irreproducible results – Insights from studies of prolylcarboxypeptidase in human cell types
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-12-14
    Malte Bayer; Nina Tsiskarishvili; Agatha Stegemann; Markus Böhm; Simone König

    α‐melanocyte stimulating hormone (α‐MSH, AcSYSMEHFRWGKPVNH2; Singh & Mukhopadhyay, 2014, D’Agostino & Diano, 2010) has a variety of biological effects in the skin such as the regulation of pigment formation and the modulation of inflammatory and immune reactions (Böhm et al., 2006; Brzoska et al., 2009). In contrast to a plethora of reports investigating the signal transduction pathways of α‐MSH, especially in melanocytes, little is known about the enzymatic degradation of this peptide. Recently, prolylcarboxypeptidase (PRCP), has been shown to serve as an endogenous regulator of the central melanocortin system by degrading α‐MSH (Wallingford et al., 2009). PRCP inactivates α‐MSH by the removal of the N‐terminal valine residue.

    更新日期:2019-12-17
  • PLX3397 inhibits the accumulation of intra‐tumoral macrophages and improves bromodomain and extra‐terminal inhibitor efficacy in melanoma
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-12-11
    Dan A. Erkes, Sheera R. Rosenbaum, Conroy O. Field, Inna Chervoneva, Jessie Villanueva, Andrew E. Aplin

    Bromodomain and extra‐terminal inhibitors (BETi) delay tumor growth, in part, through tumor cell intrinsic alterations and initiation of anti‐tumor CD8+ T‐cell responses. By contrast, BETi effects on pro‐tumoral immune responses remain unclear. Here, we show that the next‐generation BETi, PLX51107, delayed tumor growth to differing degrees in Braf V600E melanoma syngeneic mouse models. These differential responses were associated with the influx of tumor‐associated macrophages during BETi treatment. Tumors that were poorly responsive to PLX51107 showed increased influx of colony‐stimulating factor‐1 receptor (CSF‐1R)‐positive tumor‐associated macrophages. We depleted CSF‐1R+ tumor‐associated macrophages with the CSF‐1R inhibitor, PLX3397, in combination with PLX51107. Treatment with PLX3397 enhanced the efficacy of PLX51107 in poorly responsive Braf V600E syngeneic melanomas in vivo. These findings suggest that tumor‐associated macrophage accumulation limits BETi efficacy and that co‐treatment with PLX3397 can improve response to PLX51107, offering a potential novel combination therapy for metastatic melanoma patients.

    更新日期:2019-12-11
  • Decitabine limits escape from MEK inhibition in uveal melanoma
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-12-06
    Jessica Gonçalves, Michael F. Emmons, Fernanda Faião‐Flores, Andrew E. Aplin, J. William Harbour, Jonathan D. Licht, Márcia R. Wink, Keiran S. M. Smalley

    MEK inhibitors (MEKi) demonstrate anti‐proliferative activity in patients with metastatic uveal melanoma, but responses are short‐lived. In the present study, we evaluated the MEKi trametinib alone and in combination with drugs targeting epigenetic regulators, including DOT1L, EZH2, LSD1, DNA methyltransferases, and histone acetyltransferases. The DNA methyltransferase inhibitor (DNMTi) decitabine effectively enhanced the anti‐proliferative activity of trametinib in cell viability, colony formation, and 3D organoid assays. RNA‐Seq analysis showed the MEKi‐DNMTi combination primarily affected the expression of genes involved in G1 and G2/2M checkpoints, cell survival, chromosome segregation and mitotic spindle. The DNMTi‐MEKi combination did not appear to induce a DNA damage response (as measured by γH2AX foci) or senescence (as measured by β‐galactosidase staining) compared to either MEKi or DNMTi alone. Instead, the combination increased expression of the CDK inhibitor p21 and the pro‐apoptotic protein BIM. In vivo, the DNMTi‐MEKi combination was more effective at suppressing growth of MP41 uveal melanoma xenografts than either drug alone. Our studies indicate that DNMTi may enhance the activity of MEKi in uveal melanoma.

    更新日期:2019-12-07
  • The genetic architecture of vitiligo
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-12-04
    Genevieve H. L. Roberts, Stephanie A. Santorico, Richard A. Spritz

    Vitiligo is an autoimmune disease in which destruction of skin melanocytes results in patches of white skin and hair. Genome‐wide linkage studies and genome‐wide association studies in European ancestry cases identified over 50 vitiligo susceptibility loci, defining a model of melanocyte‐directed autoimmunity. Vitiligo heritability is exceedingly high, ~2/3 coming from common and ~1/3 from rare genomic variants; ~20% of vitiligo risk is environmental. Vitiligo genetic risk is polygenic, with greater additive risk in multiplex vitiligo families than simplex cases. Vitiligo age‐of‐onset is bimodal, also involving a major genetic component; a MHC enhancer haplotype confers extreme risk for vitiligo (OR 8.1) and early disease onset, increasing expression of HLA‐DQB1 mRNA and HLA‐DQ protein and thus perhaps facilitating presentation of triggering antigens. Vitiligo triggering also involves a major environmental component; dramatic delay in vitiligo age‐of‐onset, especially from 1973 to 2004, suggests that exposure or response to a key vitiligo environmental trigger diminished during this period. Together, these findings provide deep understanding of vitiligo pathogenesis and genetic architecture, suggesting that vitiligo represents a tractable model for investigating complex disease genetic architecture and predictive aspects of personalized medicine.

    更新日期:2019-12-05
  • Epidermal keratin 5 expression and distribution is under dermal influence
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-26
    Muriel Cario, Catherine Pain, Priscilla Kaulanjan‐Checkmodine, Daniela Masia, Gabriele Delia, Vincent Casoli, Pierre Costet, Jean‐François Goussot, Véronique Guyonnet‐Duperat, Alice Bibeyran, Khaled Ezzedine, Corinne Reymermier, Valérie Andre‐Frei, Alain Taieb

    Human skin melanin pigmentation is regulated by systemic and local factors. According to the type of melanin produced by melanocytes, the transfer and degradation of melanosomes differ, thus accounting for most variations between ethnicities. We made the surprising observation that in a drastically changed environment, white and black phenotypes are reversible since Caucasian skin grafted onto nude mice can become black with all black phenotypic characteristics. Black xenografts differed essentially from other grafts by the levels of epidermal FGF‐2 and keratin 5. In vitro analysis confirmed that FGF‐2 directly regulates keratin 5. Interestingly, this phenomenon may be involved in human pathology. Keratin 5 mutations in Dowling–Degos Disease (DDD) have already been associated with the pheomelanosome–eumelanosome transition. In a DDD patient, keratin 5 was expressed in the basal and spinous layers, as observed in black xenografts. Furthermore, in a common age‐related hyperpigmentation disorder like senile lentigo (SL), keratin 5 distribution is also altered. In conclusion, modulation of keratin 5 expression and distribution either due to mutations or factors may account for the development of pigmentary disorders.

    更新日期:2019-11-28
  • Functional analysis of RPS27 mutations and expression in melanoma
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-22
    Alfredo Floristán, Leah Morales, Douglas Hanniford, Carlos Martinez, Elena Castellano‐Sanz, Igor Dolgalev, Alejandro Ulloa‐Morales, Eleazar Vega‐Saenz de Miera, Una Moran, Farbod Darvishian, Iman Osman, Tomas Kirchhoff, Eva Hernando

    Next‐generation sequencing has enabled genetic and genomic characterization of melanoma to an unprecedent depth. However, the high mutational background plus the limited depth of coverage of whole‐genome sequencing performed on cutaneous melanoma samples make the identification of novel driver mutations difficult. We sought to explore the somatic mutation portfolio in exonic and gene regulatory regions in human melanoma samples, for which we performed targeted sequencing of tumors and matched germline DNA samples from 89 melanoma patients, identifying known and novel recurrent mutations. Two recurrent mutations found in the RPS27 promoter associated with decreased RPS27 mRNA levels in vitro. Data mining and IHC analyses revealed a bimodal pattern of RPS27 expression in melanoma, with RPS27‐low patients displaying worse prognosis. In vitro characterization of RPS27‐high and RPS27‐low melanoma cell lines, as well as loss‐of‐function experiments, demonstrated that high RPS27 status provides increased proliferative and invasive capacities, while low RPS27 confers survival advantage in low attachment and resistance to therapy. Additionally, we demonstrate that 10 other cancer types harbor bimodal RPS27 expression, and in those, similarly to melanoma, RPS27‐low expression associates with worse clinical outcomes. RPS27 promoter mutation could thus represent a mechanism of gene expression modulation in melanoma patients, which may have prognostic and predictive implications.

    更新日期:2019-11-22
  • GNAQQ209L expression initiated in multipotent neural crest cells drives aggressive melanoma of the central nervous system
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-20
    Oscar Urtatiz, Courtney Cook, Jenny L.‐Y. Huang, Iwei Yeh, Catherine D. Van Raamsdonk

    Primary leptomeningeal melanocytic neoplasms represent a spectrum of rare tumors originating from melanocytes of the leptomeninges, which are the inner two membranes that protect the central nervous system. Like other non‐epithelial melanocytic lesions, they bear frequent oncogenic mutations in the heterotrimeric G protein alpha subunits, GNAQ or GNA11. In this study, we used Plp1‐creERT to force the expression of oncogenic GNAQQ209L in the multipotent neural crest cells of the ventro‐medial developmental pathway, beginning prior to melanocyte cell differentiation. We found that this produces leptomeningeal melanocytic neoplasms, including cranial melanocytomas, spinal melanocytomas, and spinal melanomas, in addition to blue nevus‐like lesions in the dermis. GNAQQ209L drove different phenotypes depending upon when during embryogenesis (E9.5, E10.5, or E11.5) it was induced by tamoxifen and which Cre driver (Plp1‐creERT, Tyr‐creERT2, or Mitf‐cre) was used. Given these differences, we propose that melanocytes go through temporary phases where they become sensitive to the oncogenic effects of GNAQQ209L. R26‐fs‐GNAQQ209L; Plp1‐creERT mice will be useful for defining biomarkers for potentially aggressive leptomeningeal melanocytomas and for developing new therapeutics for advanced disease.

    更新日期:2019-11-20
  • Sequencing two Tyr::CreERT2 transgenic mouse lines
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-19
    Zackie Aktary, Andre Corvelo, Camille Estrin, Lionel Larue

    The Cre/loxP system is a powerful tool that has allowed the study of the effects of specific genes of interest in various biological settings. The Tyr::CreERT2 system allows for the targeted expression and activity of the Cre enzyme in the melanocyte lineage following treatment with tamoxifen, thus providing spatial and temporal control of the expression of specific target genes. Two independent transgenic mouse models, each containing a Tyr::CreERT2 transgene, have been generated and are widely used to study melanocyte transformation. In this study, we performed whole genome sequencing (WGS) on genomic DNA from the two Tyr::CreERT2 mouse models and identified their sites of integration in the C57BL/6 genome. Based on these results, we designed PCR primers to accurately, and efficiently, genotype transgenic mice. Finally, we discussed some of the advantages of each transgenic mouse model.

    更新日期:2019-11-20
  • The exocyst is required for melanin exocytosis from melanocytes and transfer to keratinocytes
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-19
    Hugo Moreiras, Francisco J. C. Pereira, Matilde V. Neto, Liliana Bento‐Lopes, Tiago C. Festas, Miguel C. Seabra, Duarte C. Barral

    Skin pigmentation involves the production of the pigment melanin by melanocytes, in melanosomes and subsequent transfer to keratinocytes. Within keratinocytes, melanin polarizes to the apical perinuclear region to form a protective cap, shielding the DNA from ultraviolet radiation‐induced damage. Previously, we found evidence to support the exocytosis by melanocytes of the melanin core, termed melanocore, followed by endo/phagocytosis by keratinocytes as a main form of transfer, with Rab11b playing a key role in the process. Here, we report the requirement for the exocyst tethering complex in melanocore exocytosis and transfer to keratinocytes. We observed that the silencing of the exocyst subunits Sec8 or Exo70 impairs melanocore exocytosis from melanocytes, without affecting melanin synthesis. Moreover, we confirmed by immunoprecipitation that Rab11b interacts with Sec8 in melanocytes. Furthermore, we found that the silencing of Sec8 or Exo70 in melanocytes impairs melanin transfer to keratinocytes. These results support our model as melanocore exocytosis from melanocytes is essential for melanin transfer to keratinocytes and skin pigmentation and suggest that the role of Rab11b in melanocore exocytosis is mediated by the exocyst.

    更新日期:2019-11-20
  • Extracellular acidosis triggers a senescence‐like phenotype in human melanoma cells
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-07-29
    Ines Böhme, Anja Bosserhoff

    Acidosis of the tumor microenvironment is a characteristic of solid tumors such as malignant melanoma. Main causes of the extracellular acidification are metabolic alterations in cancer cells. While numerous studies showed that acidosis promotes tumor invasiveness, metastasis, and neoangiogenesis resulting in malignant progression, contrary data reported that acidosis induces cell apoptosis, inhibits cell proliferation, and mediates cell autophagy. Here, we show that low pH (pH 6.7) induces senescent/quiescent phenotype in melanoma cells after long‐time treatment defined by induction of SA‐ß‐galactosidase, upregulation of p21, G1/G0 cell cycle arrest, and reduction of proliferation. Moreover, we revealed that extracellular acidosis triggers the inhibition of eIF2α and subsequently the activation of ATF4 expression, a key component of the integrated stress response (ISR), indicating an acid‐mediated translation reprogramming. Interestingly, we also demonstrated that acidosis represses microphthalmia‐associated transcription factor (MITF) and activates the expression of the receptor tyrosine kinase AXL. This MITFlow/AXLhigh phenotype is correlated with drug resistance and therapeutic outcome in melanoma. Our results suggest that acidosis is an important microenvironmental factor triggering phenotypic plasticity and promoting tumor progression.

    更新日期:2019-11-18
  • MX 2 is a novel regulator of cell cycle in melanoma cells
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-13
    Marina Juraleviciute, Joanna Pozniak, Jérémie Nsengimana, Mark Harland, Juliette Randerson‐Moor, Patrik Wernhoff, Assia Bassarova, Geir Frode Øy, Gunhild Trøen, Vivi Ann Flørenes, David Timothy Bishop, Meenhard Herlyn, Julia Newton‐Bishop, Ana Slipicevic

    MX2 protein is a dynamin‐like GTPase2 that has recently been identified as an interferon‐induced restriction factor of HIV‐1 and other primate lentiviruses. A single nucleotide polymorphism (SNP), rs45430, in an intron of the MX2 gene, was previously reported as a novel melanoma susceptibility locus in genome‐wide association studies. Functionally, however, it is still unclear whether and how MX2 contributes to melanoma susceptibility and tumorigenesis. Here, we show that MX2 is differentially expressed in melanoma tumors and cell lines, with most metastatic cell lines showing lower MX2 expression than primary melanoma cell lines and melanocytes. Furthermore, high expression of MX2 RNA in primary melanoma tumors is associated with better patient survival. Overexpression of MX2 reduces in vivo proliferation partially through inhibition of AKT activation, suggesting that it can act as a tumor suppressor in melanoma. However, we have also identified a subset of melanoma cell lines with high endogenous MX2 expression where downregulation of MX2 leads to reduced proliferation. In these cells, MX2 downregulation interfered with DNA replication and cell cycle processes. Collectively, our data for the first time show that MX2 is functionally involved in the regulation of melanoma proliferation but that its function is context‐dependent.

    更新日期:2019-11-13
  • GABA‐A receptor and mitochondrial TSPO signaling act in parallel to regulate melanocyte stem cell quiescence in larval zebrafish
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-11
    James R. Allen, James B. Skeath, Stephen L. Johnson

    Tissue regeneration and homeostasis often require recruitment of undifferentiated precursors (adult stem cells; ASCs). While many ASCs continuously proliferate throughout the lifetime of an organism, others are recruited from a quiescent state to replenish their target tissue. A long‐standing question in stem cell biology concerns how long‐lived, non‐dividing ASCs regulate the transition between quiescence and proliferation. We study the melanocyte stem cell (MSC) to investigate the molecular pathways that regulate ASC quiescence. Our prior work indicated that GABA‐A receptor activation promotes MSC quiescence in larval zebrafish. Here, through pharmacological and genetic approaches we show that GABA‐A acts through calcium signaling to maintain MSC quiescence. Unexpectedly, we identified translocator protein (TSPO), a mitochondrial membrane‐associated protein that regulates mitochondrial function and metabolic homeostasis, as a parallel regulator of MSC quiescence. We found that both TSPO‐specific ligands and induction of gluconeogenesis likely act in the same pathway to promote MSC activation and melanocyte production in larval zebrafish. In contrast, TSPO and gluconeogenesis appear to act in parallel to GABA‐A receptor signaling to regulate MSC quiescence and vertebrate pigment patterning.

    更新日期:2019-11-13
  • Autophagy induction can regulate skin pigmentation by causing melanosome degradation in keratinocytes and melanocytes
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-11
    Ji Young Kim, Jihee Kim, Yuri Ahn, Eun Jung Lee, Shinwon Hwang, Abdurrahman Almurayshid, Keedon Park, Hwa‐Jee Chung, Heung Jae Kim, Si‐Hyung Lee, Myung‐Shik Lee, Sang Ho Oh

    Autophagy regulates cellular turnover by disassembling unnecessary or dysfunctional constituents. Recent studies demonstrated that autophagy and its regulators play a wide variety of roles in melanocyte biology. Activation of autophagy is known to induce melanogenesis and regulate melanosome biogenesis in melanocytes. Also, autophagy induction was reported to regulate physiologic skin color via melanosome degradation, although the downstream effectors are not yet clarified. To determine the role of autophagy as a melanosome degradation machinery, we administered several autophagy inducers in human keratinocytes and melanocytes. Our results showed that the synthetic autophagy inducer PTPD‐12 stimulated autophagic flux in human melanocytes and in keratinocytes containing transferred melanosomes. Increased autophagic flux led to melanosome degradation without affecting the expression of MITF. Furthermore, the color of cell pellets of both melanocytes and keratinocytes was visibly lightened. Inhibition of autophagic flux by chloroquine resulted in marked attenuation of PTPD‐12‐induced melanosome degradation, whereas the expression of melanogenesis pathway genes and proteins remained unaffected. Taken together, our results suggest that the modulation of autophagy can contribute to the regulation of melanocyte biology and skin pigmentation.

    更新日期:2019-11-11
  • Switch to checkpoint inhibition after targeted therapy at time of progression or during ongoing response: A retrospective single‐centre experience in patients with BRAF‐mutated melanoma
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-10
    Irene L. M. Reijers, Elisa A. Rozeman, Sofie Wilgenhof, Johannes V. van Thienen, John B. A. G. Haanen, Christian U. Blank

    BRAF + MEK inhibition is preferentially applied as first‐line therapy in BRAF V600‐mutated melanoma patients with unfavourable prognostic features, due to the ability of targeted therapy (TT) to induce rapid symptom control, decrease tumour burden and normalize lactate dehydrogenase (LDH) levels. In addition, short‐term TT transiently increases tumour antigen presentation and tumour influx of T cells. Therefore, it might be favourable to switch TT to checkpoint inhibition (CPI) before progression (PD). We retrospectively analysed melanoma patients treated first line with TT (TT1) and who subsequently switched to CPI during response to TT (sDR group) or at progression upon TT (sPD group). We identified 74 patients (n = 37 sDR group and n = 37 sPD group). ORR to CPI was 27.0% in the sDR group versus 24.3% in the sPD group (p = .790). Median was PFS 2.5 months versus 1.2 months (p = .145), and median OS was 30.6 versus 14.1 months (p = .007). After adjusting for baseline differences and known prognostic factors, hazard ratios (HRs) favouring sDR were 0.89 for PFS upon CPI (p = .956) and 0.48 for OS (p = .055). Thus, patients switching to CPI during ongoing clinical benefit from TT do not have an inferior outcome. Due to baseline imbalances and small patient population, a favourable trend for the sDR group can be hypothesized only.

    更新日期:2019-11-11
  • Targeted Therapy and Immunotherapy: Emerging Biomarkers in Metastatic Melanoma
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-09
    Patricia M. LoRusso, Kurt Schalper, Jeffrey Sosman

    Targeted therapy directed against oncogenic BRAF mutations and immune checkpoint inhibitors have transformed melanoma therapy over the past decade and prominently improved patient outcomes. However, not all patients will respond to targeted therapy or immunotherapy and many relapse after initially responding to treatment. This unmet need presents two major challenges. First, can we elucidate novel oncogenic drivers to provide new therapeutic targets? Second, can we identify patients who are most likely to respond to current therapeutic strategies in order to both more accurately select populations and avoid undue drug exposure in patients unlikely to respond? In an effort to evaluate the current state of the field with respect to these questions, we provide an overview of some common oncogenic mutations in patients with metastatic melanoma and ongoing efforts to therapeutically target these populations, as well as a discussion of biomarkers for response to immune checkpoint inhibitors—including tumor programmed death ligand 1 expression and the future use of neoantigens as a means of truly personalized therapy. This information is becoming important in treatment decision making and provides the framework for a treatment algorithm based on the current landscape in metastatic melanoma.

    更新日期:2019-11-11
  • Combined ipilimumab and nivolumab first‐line and after BRAF‐targeted therapy in advanced melanoma
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2019-11-02
    Robert Mason, Helen C. Dearden, Bella Nguyen, Jennifer S. Oon, Jessica Louise Smith, Manreet Randhawa, Andrew Mant, Lydai Warburton, Serigne Lo, Tarek Meniawy, Alexander Guminski, Phillip Parente, Sayed Ali, Andrew Haydon, Georgina V. Long, Matteo S. Carlino, Michael Millward, Victoria G. Atkinson, Alexander M. Menzies

    The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of serine/threonine‐protein kinase B‐Raf (BRAF)‐targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment‐naïve and 22% failed first‐line BRAF/MEK inhibitors. Treatment‐related adverse events occurred in 67% of patients, grade 3–5 in 38%. The overall objective response rate was 41%, 57% in treatment‐naïve and 21% in BRAF/MEK failure patients. Median progression‐free survival was 4.0 months (95% CI, 3.0–6.0) in the whole cohort, 11.0 months (95% CI, 6.0‐NR) in treatment‐naïve and 2.0 months (95% CI, 1.4–4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real‐world population. While first‐line efficacy appears comparable to trial populations, BRAF‐mutant patients failing prior BRAF/MEK inhibitors show less response.

    更新日期:2019-11-04
  • Control of NF-kB activity in human melanoma by bromodomain and extra-terminal protein inhibitor I-BET151.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2014-06-14
    Stuart J Gallagher,Branka Mijatov,Dilini Gunatilake,Kavitha Gowrishankar,Jessamy Tiffen,Wilmott James,Lei Jin,Gulietta Pupo,Carleen Cullinane,Grant A McArthur,Peter J Tummino,Helen Rizos,Peter Hersey

    The transcription factor NF-kappaB (NF-kB) is a key regulator of cytokine and chemokine production in melanoma and is responsible for symptoms such as anorexia, fatigue, and weight loss. In addition, NF-kB is believed to contribute to progression of the disease by upregulation of cell cycle and anti-apoptotic genes and to contribute to resistance against targeted therapies and immunotherapy. In this study, we have examined the ability of the bromodomain and extra-terminal (BET) protein inhibitor I-BET151 to inhibit NF-kB in melanoma cells. We show that I-BET151 is a potent, selective inhibitor of a number of NF-kB target genes involved in induction of inflammation and cell cycle regulation and downregulates production of cytokines such as IL-6 and IL-8. SiRNA studies indicate that BRD2 is the main BET protein involved in regulation of NF-kB and that I-BET151 caused transcriptional downregulation of the NF-kB subunit p105/p50. These results suggest that BET inhibitors may have an important role in treatment of melanoma where activation of NF-kB may have a key pathogenic role.

    更新日期:2019-11-01
  • Evolutionary and biomedical consequences of internal melanins.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2014-05-21
    Sylvain Dubey,Alexandre Roulin

    The adaptive function of melanin located in the integument is well known. Although pigments are also deposited in various internal organs, their function is unclear. A review of the literature revealed that 'internal melanin' protects against parasites, pollutants, low temperature, oxidative stress, hypoxemia and UV light, and is involved in the development and function of organs. Importantly, several studies have shown that the amount of melanin deposited on the external body surface is correlated with the amount located inside the body. This finding raises the possibility that internal melanin plays more important physiological roles in dark than light-colored individuals. Internal melanin and coloration may therefore not evolve independently. This further emphasizes the major role played by indirect selection in evolutionary processes.

    更新日期:2019-11-01
  • Tetraspanin 3c requirement for pigment cell interactions and boundary formation in zebrafish adult pigment stripes.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2014-04-16
    Shinya Inoue,Shigeru Kondo,David M Parichy,Masakatsu Watanabe

    Skin pigment pattern formation in zebrafish requires pigment-cell autonomous interactions between melanophores and xanthophores, yet the molecular bases for these interactions remain largely unknown. Here, we examined the dali mutant that exhibits stripes in which melanophores are intermingled abnormally with xanthophores. By in vitro cell culture, we found that melanophores of dali mutants have a defect in motility and that interactions between melanophores and xanthophores are defective as well. Positional cloning and rescue identified dali as tetraspanin 3c (tspan3c), encoding a transmembrane scaffolding protein expressed by melanophores and xanthophores. We further showed that dali mutant Tspan3c expressed in HeLa cell exhibits a defect in N-glycosylation and is retained inappropriately in the endoplasmic reticulum. Our results are the first to identify roles for a tetraspanin superfamily protein in skin pigment pattern formation and suggest new mechanisms for the establishment and maintenance of zebrafish stripe boundaries.

    更新日期:2019-11-01
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  • Senescence-escape in melanoma.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2012-08-18
    Wenjin Liu,Norman E Sharpless

    更新日期:2019-11-01
  • 更新日期:2019-11-01
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  • Pigmentation or transparency? Camouflage tactics in deep-sea cephalopods.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2012-05-26
    Lydia M Mäthger,Roger T Hanlon

    更新日期:2019-11-01
  • Active surrender.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2012-05-26
    Eric A Collisson

    更新日期:2019-11-01
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  • Targeting leucine addiction and autophagy in melanoma.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2012-04-11
    Maria T Diaz-Meco

    更新日期:2019-11-01
  • 更新日期:2019-11-01
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  • Melanocytes and melanoma: hooked on elongation.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2012-04-11
    James A Lister

    更新日期:2019-11-01
  • A fitness model for melanoma-initiating cells.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2012-04-11
    Bradley J Kubick,Dennis R Roop

    更新日期:2019-11-01
  • Coding genes join the non-coding world.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2012-04-10
    Sergei A Manakov,Jing Crystal Zhao

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • New dream team for melanoma therapy.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2012-03-31
    Meenhard Herlyn

    更新日期:2019-11-01
  • A DUB for MITF: no myth, some dubiety.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2011-11-15
    Serge Y Fuchs

    更新日期:2019-11-01
  • Serine biosynthesis: fuel for the melanoma cell growth engine.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2011-11-15
    Stephen G Dann,Robert T Abraham

    更新日期:2019-11-01
  • Induction of senescence in melanoma: thinking outside the cell.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2011-11-15
    Narendra Wajapeyee,Michael R Green

    更新日期:2019-11-01
  • Interpretation of complex phenotypes: lessons from the Mitf gene.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2011-08-09
    Eiríkur Steingrímsson

    Mutations provide important structure–function relationships by allowing the correlation of phenotypes to the underlying genotypes. Knockout mutations that lead to loss-of-function are important and informative in this respect. However, spontaneous and induced mutations sometimes provide surprising phenotypes, which lead to unexpected functional insights and novel biochemical pathways, especially when multiple mutations(alleles) exist at a locus. An excellent example is provided by the microphthalmia (Mitf) locus in the mouse.The multiple Mitf alleles have their own phenotypic properties, most of which have been explained by the underlying mutation. However, one allele, the Mitf (Mi-White) (Mitf (Mi-Wh)) mutation, exhibits phenotypes that have not yet been fully explained. Here, the molecular, genetic, and phenotypic properties of this mutation are reviewed and an attempt made to explain the underlying biochemical reason for its observed effects.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Unwelcome guests: macrophages promote UV-induced melanoma.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2011-04-26
    William E Damsky,Marcus Bosenberg

    更新日期:2019-11-01
  • (Mela)statin' the not so obvious: tumor suppressor hidden in intron.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2011-04-26
    Ashley M Poenitzsch,Vijayasaradhi Setaluri,Vladimir S Spiegelman

    更新日期:2019-11-01
  • MITF: the power and the glory.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2011-04-26
    Keith S Hoek

    更新日期:2019-11-01
  • Melanoma and viagra: an unexpected connection.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2011-02-04
    Devarati Mitra,Kathleen C Robinson,David E Fisher

    更新日期:2019-11-01
  • Downregulated melanogenic paracrine cytokine linkages in hypopigmented palmoplantar skin.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2008-12-17
    Junichi Hasegawa,Yasufumi Goto,Hiroshi Murata,Minoru Takata,Toshiaki Saida,Genji Imokawa

    The hypo-pigmentation of human skin on the palms and the soles compared with other areas of the body has recently been reported to be due to mesenchymal-epithelial interactions via a fibroblast-derived factor, dickkopf 1, an inhibitor of the canonical Wnt signaling pathway. Recently, it has been reported that keratinocytes play a significant role in skin color determination by producing cytokines involved in melanogenesis. Thus, we hypothesized that the downregulated expression of keratinocyte- or fibroblast-derived melanogenic cytokines may also be responsible for the decreased function of palmoplantar (PP) melanocytes in addition to the suppressive effects of dickkopf 1 on melanogenic function in epidermal melanocytes. Immunohistochemistry revealed that the number of tyrosinase, S100alpha, c-KIT, endothelin B receptor (ETBR), SOX10, and microphthalmia-associated transcription factor (MITF) immuno-positive melanocytes is significantly reduced in PP epidermis. In contrast, dopa-histochemistry demonstrated no substantial reduction in melanocyte populations in PP epidermis. Real-time RT-PCR revealed that the expression of stem cell factor (SCF) and endothelin (ET)-1 mRNAs in PP skin was significantly downregulated. In parallel, immunohistochemistry revealed that SCF and ET-1 immuno-staining was markedly attenuated in PP skin. Western blotting revealed that the expression of SCF, c-KIT, and MITF-M proteins was significantly decreased in PP skin. These findings suggest the possibility that downregulation of ET-1/SCF/receptor linkages is also associated with the decreased function of melanocytes in PP skin.

    更新日期:2019-11-01
  • Lymphangiogenesis: From passive disseminator to dynamic metastatic enabler.
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2017-08-02
    Eva Pérez-Guijarro,Glenn Merlino

    更新日期:2019-11-01
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