IL-21 promoting angiogenesis contributes to the development of psoriasis.

BACKGROUND: Elevated IL-21 expression which can effectively induce Th17 cell differentiation has been implicated in the pathogenesis of psoriasis, but its role in angiogenesis remains poorly understood. METHODS: PASI and PSI score assessment was applied to evaluate the severity of psoriatic lesions. The expression of IL-21, IL-21 receptor (IL-21R), CD31, VEGFA, MMP-9, and ICAM-1 in skin was determined by immunohistochemistry or quantitative real-time polymerase chain reaction. The serum level of IL-21 was measured by enzyme-linked immunosorbent assay (ELISA). Then, their correlation was analyzed statistically. Human umbilical vein endothelial cells (HUVECs) cocultured with conditional medium from normal human epidermal keratinocytes (NHEKs) were treated with IL-21 and/or M5 cocktail (mixture of IL-1α, IL-17A, IL-22, TNF-α, and oncostatin M). The migration and tube formation of HUVECs were detected, and the levels of VEGFA, MMP-9, and ICAM-1 in NHEKs were measured by Western blotting or ELISA. RESULTS: Increased IL-21 and IL-21R expression was observed in psoriatic sera or skin specimens, with IL-21R mainly locating in keratinocytes and IL-21 in immune cells. Pearson analysis showed significantly positive correlation between IL-21/IL-21R and erythema scores/microvessel density in psoriatic lesions. Moreover, the expression of proangiogenic genes, VEGFA, ICAM-1, and MMP-9 was upregulated in skins of psoriasis. Additionally, in M5 microenvironment, migration and tube formation could be magnified in HUVECs using IL-21 pre-treated NHEK medium. Mechanically, the co-stimulation of IL-21 and M5 to NEHKs increased the expression of ICAM-1. CONCLUSION: IL-21 could regulate keratinocytes to secrete ICAM-1, thereby promoting angiogenesis in psoriasis.

Single-cell transcriptomics reveals peripheral immune responses in non-segmental vitiligo.

Background: Vitiligo is a common autoimmune depigmented dermatology due to destruction of melanocytes. Much evidence suggests that vitiligo is associated with systemic immune activation. Previous studies have focused on immune cell infiltration in and around lesion areas, but few studies have investigated the cell types and function of circulating immune cells in peripheral blood. Here, single cell RNA-sequencing (scRNA-seq) was used to investigate the mechanisms of peripheral immune responses in vitiligo patients. Methods: Peripheral blood was collected from five patients with progressive non-segmental vitiligo and three healthy controls. Peripheral blood mononuclear cells (PBMCs) were obtained by Ficoll-Paque density gradient centrifugation, and scRNA-seq was performed on isolated cell populations to obtain single cell transcriptomes and characterize important genes and intracellular signaling pathways. The key findings were validated with qPCR and flow cytometry assays. Results: We identified 10 major cell types by scRNA-seq. Among these cell types, neutrophils were specifically observed in our scRNA-seq data from PBMCs. Peripheral blood effector CD8+ T cells from vitiligo patients did not show significant differences at the transcriptome level compared with healthy controls, whereas regulatory T cells showed pro-inflammatory TH1-like properties. Innate immune cells, including natural killer cells and dendritic cells, showed increased antigen processing and presentation as well as upregulated interferon responses. B cells, monocytes, and neutrophils all showed activation. B cells, especially memory B cells, had upregulated expression of genes related to humoral immunity. Monocytes showed production of proinflammatory cytokines and chemokines. Neutrophils showed strong chemokine ligand-receptor (L-R) pair (CXCR8-CXCR2) autocrine signaling pathway. Conclusion: This study revealed the genetic profile and signaling pathway characteristics of peripheral blood immune cells in vitiligo patients, providing new insights into its pathogenesis, which may facilitate identification of potential therapeutic targets.

Metagenomic sequencing reveals altered gut microbial compositions and gene functions in patients with non-segmental vitiligo.

BACKGROUND: Vitiligo has been correlated with an abnormal gut microbiota. We aimed to systematically identify characteristics of the gut microbial compositions, genetic functions, and potential metabolic features in patients with non-segmental vitiligo. METHODS: Twenty-five patients with non-segmental vitiligo and 25 matched healthy controls (HCs) were enrolled. Metagenomic sequencing and bioinformatic analysis were performed to determine the gut microbiota profiles. Differences in gut microbiota diversity and composition between patients with vitiligo and HCs were analyzed. Gene functions and gut metabolic modules were predicted with the Kyoto Encyclopedia of Gene and Genomes (KEGG) and MetaCyc databases. RESULTS: Compared with HCs, alpha diversity of intestinal microbiome in vitiligo patients was significantly reduced. At the species level, the relative abundance of Staphylococcus thermophiles was decreased, and that of Bacteroides fragilis was increased in patients with vitiligo compared with those of the HCs. Linear discriminant analysis (LDA) effect size (LEfSe) analysis revealed representative microbial markers of Lachnospiraceae_bacterium_BX3, Massilioclostridium_coli, TM7_phylum_sp_oral_taxon_348 and Bacteroides_fragilis for patients with vitiligo. KEGG gene function analysis showed that the NOD-like receptor signaling pathway was significantly enriched in patients with vitiligo. Gut metabolic modules (GMMs) analysis showed that cysteine degradation was significantly down-regulated, and galactose degradation was up-regulated in patients with vitiligo. A panel of 28 microbial features was constructed to distinguish patients with vitiligo from HCs. CONCLUSIONS: The gut microbial profiles and genetic functions of patients with vitiligo were distinct from those of the HCs. The identified gut microbial markers may potentially be used for earlier diagnosis and treatment targets.

PARP1 Is a Prognostic Marker and Targets NFATc2 to Promote Carcinogenesis in Melanoma.

Background: Melanoma is the most lethal skin tumor. PARP1 plays an oncogenic role in tumors, but the mechanism of PARP1 in melanoma remains unclear. Explicating the functional mechanism of PARP1 might highlight new targets for improving the survival rate of melanoma patients. Methods: The expression level of PARP1 and its correlation with prognosis of melanoma were examined using the TCGA dataset, the GEO12391 dataset, and western blot analysis. The differentially expressed genes (DEGs) following PARP1 intervention were identified via microarray analyses. GSEA, GO, and KEGG pathway enrichment analyses of the DEGs were performed. Theses DEGs were also compared with PARP1-related DEGs in the GEO59455 dataset and correlation analyses were performed to identify the intersection of the two gene sets to identify PARP1 target genes. The regulatory relationship between PARP1 and its target gene NFATc2 was examined by Western blot analysis and RT-qPCR. A CCK8 assay was used to determine the biological role of PARP1 and its target, NFATc2, in melanoma. Results: We demonstrated that PARP1 was overexpressed in both melanoma tissues and melanoma cell lines, and that upregulated expression of PARP1 was associated with higher pathological stages and unfavorable prognosis of melanoma. Five genes (NFATc2, ITGAX, CYP26B1, SYT17, and VGF) were identified as PARP1 target genes, and NFATc2 expression was confirmed to be regulated by PARP1. A CCK8 assay showed that by down-regulating expression of PARP1 or NFATc2 that melanoma proliferation was inhibited. Conclusions: Taken together, the results of this study demonstrated that PARP1 expression is a prognostic marker and contributes to melanoma proliferation through the regulation of NFATc2.

Corrigendum: LNMAT1 Promotes Invasion-Metastasis Cascade in Malignant Melanoma by Epigenetically Suppressing CADM1 Expression.

[This corrects the article DOI: 10.3389/fonc.2019.00569.].

[Corrigendum] Linc00961 inhibits the proliferation and invasion of skin melanoma by targeting the miR­367/PTEN axis.

Following the publication of the above article, the authors have informed us that they found errors in two of the published figures that occurred whilst compiling them. In Fig. 8, the representative images selected for the migratory and invasive A375 cells in the Lv­control + miR­367 NC group experiments were found to be overlapping. After having consulted their original data, the authors noted that the error arose during the data acquisition process, and an area of the image captured for the migratory A375 cells was inadvertently re­used as the invasive A375 cells for the Lv­control + miR­367 NC group. Likewise, in Fig. S3, the error arose during the process of assembling the data in the figure: In this case, the (A) migratory and (B) invasive cell images shown for the SK­MEL­28/Lv­LINC00961 + PTEN siRNA experiments were selected incorrectly. The revised versions of Figs. 8 and S3 are shown on the next page. The authors regret that these errors went unnoticed prior to publication, and thank the Editor of International Journal of Oncology for allowing them this opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they also apologize to the readership of the journal for any inconvenience caused. [the original article was published in International Journal of Oncology 55: 708­720, 2019; DOI: 10.3892/ijo.2019.4848].

Topical Treatment of Colquhounia Root Relieves Skin Inflammation and Itch in Imiquimod-Induced Psoriasiform Dermatitis in Mice.

Itch is one of the major clinical manifestations of psoriasis, which is closely related with neurogenic inflammation and difficult to control. Colquhounia Root (CR) is a Chinese herb exhibiting broad bioactivities on anti-inflammation. This study was designed to explore the antipsoriatic and anti-itch potential of CR and its underlying mechanisms. Mice in a model of imiquimod-induced psoriasiform dermatitis were treated topically with CR for 7 days, and the severity of skin lesions and itch was significantly ameliorated. CR reduced the inflammatory cell infiltration, as well as mast cells in skins. Particularly, the expression of inflammatory cytokines and chemokine including Il17a, Il22, and Ccl20 and itch-related molecules such as SP, CGRP, and NGF in lesions were decreased in diseased mice upon application with CR. The normal human epidermal keratinocytes were stimulated with the M5 cytokine cocktail, the mixture of IL-17A, IL-22, Oncostatin M, IL-1α, and TNF-α, and cell viability and mRNA expression levels of inflammatory factors and itch-related molecules were measured after being treated with CR. We found that CR inhibited both cell hyperproliferation and overexpression of inflammatory cytokines and itch-related molecules in vitro. Altogether, we conclude that CR relieves psoriatic lesions and itch via controlling immunological and neurogenic inflammation.

Inhibition of spindle and kinetochore associated complex subunit 3 suppresses the proliferation and invasion and induced the apoptosis of cutaneous melanoma by affecting the PI3K/Akt pathway.

Spindle and kinetochore-associated complex subunit 3 (SKA3) is reportedly a key contributor to the progression of various cancers. The present work aimed to evaluate the possible role of SKA3 in cutaneous melanoma (CM). A high SKA3 level was found in CM tissues and predicted a poor prognosis. SKA3 silencing markedly repressed the proliferation, invasion, and epithelial-mesenchymal transition and induced the apoptosis of CM cells. SKA3 silencing decreased the phosphorylation of PI3K and Akt. Akt inhibition markedly reversed SKA3 overexpression-induced oncogenic effects on CM cells. SKA3 silencing significantly prohibited the formation and growth of CM-derived xenograft tumors in nude mice in vivo. Our findings demonstrated SKA3 inhibition repressed the progression of CM by downregulating the PI3K/Akt pathway. This study indicates that SKA3 has potential as an anticancer candidate for CM.

Zwint facilitates melanoma progression by promoting c-Myc expression.

ZW10 interactor (Zwint) is upregulated in various types of tumors and exerts a carcinogenic effect. However, little is known about the expression profile, function and molecular mechanisms of action of Zwint in melanoma. Therefore, the aim of the present study was to investigate the expression levels of Zwint in melanoma cell lines and tissues. It was revealed that Zwint was highly expressed in melanoma samples. Functional experiments indicated that Zwint knockdown suppressed the proliferation and migration of A375 melanoma cells. Further mechanistic studies demonstrated that Zwint knockdown decreased the protein expression levels of c-Myc, MMP-2, Slug, mTOR, phosphorylated (p)-mTOR, p-p38 and fibronectin, while it increased the protein expression levels of E-cadherin and MMP-9. Among these genes, c-Myc, MMP-2 and Slug were overexpressed to investigate their effects on cell proliferation following Zwint knockdown. The results demonstrated that overexpression of c-Myc, but not MMP-2 or Slug, rescued the effects of Zwint knockdown on melanoma cell proliferation and migration. Taken together, the results of the present study suggested that Zwint may act as an oncogene in melanoma by regulating c-Myc expression.

Scutellarin Suppresses RPMI7951 Melanoma Cell Proliferation by Targeting TOPK.

BACKGROUND: T-LAK cell-Originated Protein Kinase (TOPK) belongs to the serine/threonine protein kinase family. It is highly expressed in RPMI7951 melanoma cells. Scutellarin (SCU) is an active ingredient extracted from Erigeron breviscapus (Vant.) Hand.-Mazz. Its main physiological functions are related to its anti-inflammatory and antitumour activities. METHODS: The relationship between SCU and TOPK was assessed by molecular docking, an in vitro binding assay and an in vitro kinase assay. The effect of SCU on RPMI7951 cells was detected by MTS and soft agar assays. TOPK knockdown was induced by lentiviral infection. The TOPK downstream signalling pathway was detected by western blot and immunohistochemical analyses in vitro and in vivo. RESULTS: SCU was found to directly bind with TOPK and inhibit TOPK activity in vitro. SCU inhibited the proliferation and colony formation of RPMI7951 cells in a dose-dependent manner. Silencing TOPK decreased the sensitivity of colon cancer cells to SCU. SCU inhibited the phosphorylation levels of Extracellular Regulated protein Kinases 1/2 (ERK1/2) and histone H3 in a time- and dose-dependent manner in RPMI7951 cells. In addition, SCU inhibited the growth of xenograft tumours of RPMI7951 cells and decreased the phosphorylation levels of extracellular regulated protein kinases 1/2 and histone H3 in vivo. CONCLUSION: The results showed that SCU exerts promising antitumour effects on human RPMI7951 cells by inhibiting the activity of TOPK.

Elevated IL-22 in psoriasis plays an anti-apoptotic role in keratinocytes through mediating Bcl-xL/Bax.

IL-22 is known to mediate inflammation in psoriasis, while IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling. However, the function of IL-22 in regulating apoptosis in psoriasis remains poorly understood. In this study, we found that IL-22/IL-22R1 in lesional skin and IL-22 in serum from psoriatic patients were highly upregulated compared with healthy controls, while IL-22BP was not changed. Correlations between IL-22/IL-22R1 levels and the thickness of psoriatic lesions suggested that IL-22 might positively regulate abnormal hyperplasia in psoriasis. Apoptotic keratinocytes were increased only in stratum corneum, but not in spinous and basal layers of psoriasis. Moreover, IL-22 promoted cell viability in human epidermal keratinocytes (HEKs). The apoptosis induced by TNF-α and IFN-γ was inhibited in HEKs treated with IL-22, since that IL-22 upregulated Bcl-xL and downregulated Bax production in HEKs in the presence of TNF-α and IFN-γ. In addition, IL-22BP could counteract the anti-apoptotic effect of IL-22. Our finding demonstrates that IL-22 might play an anti-apoptosis role on keratinocytes to balance cell proliferation and apoptosis in psoriatic epidermis.

Linc00961 inhibits the proliferation and invasion of skin melanoma by targeting the miR­367/PTEN axis.

Long intergenic noncoding RNA 00961 (Linc00961) has been identified as a tumor suppressor in various types of cancer. However, the critical roles of Linc00961 in the carcinogenesis and progression of skin melanoma (SM) are yet to be fully elucidated. The present study revealed via reverse transcription­quantitative PCR analysis that Linc00961 was downregulated in the tissues of patients with SM compared with benign nevi, and in A375, A2058 and SK­MEL­28 cell lines compared with human melanocytes. Furthermore, overexpression of Linc00961 inhibited cell proliferation, and promoted the apoptosis of A375 and SK­MEL­28 cells in vitro and in vivo, as determined by Cell Counting Kit­8 and flow cytometry assays, and tumor xenograft studies, respectively. Overexpression of Linc00961 also led to an attenuation of the migration and invasive capabilities of A375 and SK­MEL­28 cells, measured using Transwell assays. Functionally, it was demonstrated that Linc00961 acted as a competing endogenous RNA (ceRNA) by competitively sponging microRNA­367 (miR­367) in A375 and SK­MEL­28 cells; restoration of miR­367 rescued the inhibitory effects of Linc00961 on A375 and SK­MEL­28 cells. Finally, it was observed that phosphate and tension homology deleted on chromosome 10 (PTEN), an established target of miR­367 in A375 and SK­MEL­28 cells, was positively regulated by Linc00961, and its inhibition reversed the inhibitory effects of Linc00961 on the proliferation and invasion of A375 and SK­MEL­28 cells. Collectively, the present study revealed that Linc00961 was downregulated in SM, and furthermore, Linc00961 was identified as a ceRNA that inhibits the proliferation and invasion of A375 and SK­MEL­28 cells by modulating the miR­367/PTEN axis.

LNMAT1 Promotes Invasion-Metastasis Cascade in Malignant Melanoma by Epigenetically Suppressing CADM1 Expression.

The invasion-metastasis cascade is one of the most important factors relating to poor survival and prognosis of malignant melanoma (MM) patients. Long non-coding RNA lymph node metastasis associated transcript 1 (LNMAT1) is a key regulator in lymph node metastasis of multiple cancer types, but the roles and underlying mechanisms of LNMAT1 in the invasion-metastasis cascade of MM remain unclear. In the present study, we aimed to investigate the expression and function of LNMAT1 in MM. Here, we found that LNMAT1 was upregulated in MM tissues and cells, and its expression levels were further enhanced in MM patients with lymph node metastasis and metastatic MM cells. Using loss-of-function assays, we found that LNMAT1 promoted cell migration and invasion and lung metastasis in MM in vitro and in vivo. Moreover, we found that cell adhesion molecule 1 (CADM1), the established tumor suppressor in MM, was the downstream target of LNMAT1. Mechanistically, LNMAT1 epigenetically suppressed CADM1 expression by recruiting EZH2, the key regulator of trimethylation of histone H3 at lysine 27 (H3K27me3), to the CADM1 promoter, resulting in transcriptional inhibition of CADM1. Lastly, rescue assays demonstrated that LNMAT1 promoted cell migration and invasion of MM by suppressing CADM1 expression. Our findings elucidate a new mechanism for LNMAT1-mediated invasion-metastasis cascade in MM and suggest that LNMAT1 may be a new therapeutic target and prognostic predictor for MM.

Glycyrrhizin protects human melanocytes from H2O2­induced oxidative damage via the Nrf2­dependent induction of HO­1.

Oxidative stress serves a critical role in melanocyte death and is considered to be a major cause of vitiligo. The nuclear factor E2­related factor 2 (Nrf2) signaling pathway has an important role in the antioxidative stress mechanisms of melanocytes. Glycyrrhizin (GR) is a derivative of herbal medicines used to treat hepatitis and allergic disease due to its antiviral and anti­allergy effects. GR also activates Nrf2 and induces the expression of heme oxygenase (HO)­1 in macrophages. Whether GR can protect human melanocytes from oxidative stress remains unknown. The present study investigated the potential protective effects of GR against oxidative stress in human melanocytes and the mechanisms involved. Following exposure to 0.5 mM hydrogen peroxide (H2O2), human primary melanocytes were treated with 1 mM GR. Cell viability was determined using a Cell Counting Kit­8 assay, and apoptosis was evaluated by flow cytometry. GR treatment significantly improved cell viability, reduced the apoptotic rate of melanocytes and reduced the level of reactive oxygen species in human melanocytes. Furthermore, GR induced the nuclear translocation of Nrf2 and induced the expression of HO­1 in melanocytes. The knockdown of Nrf2 by small interfering RNA or the inhibition of HO­1 by ZnPP reversed the protective effect of GR on melanocytes against H2O2­induced cytotoxicity and apoptosis. These data demonstrate that GR protects human melanocytes from H2O2­induced oxidative damage via the Nrf2­dependent induction of HO­1, providing evidence for the application of GR in the treatment of vitiligo.

Gossypetin Inhibits Solar-UV Induced Cutaneous Basal Cell Carcinoma Through Direct Inhibiting PBK/TOPK Protein Kinase.

BACKGROUND: Skin photoaging, skin inflammation and skin cancer are related with excessive exposure to solar UV. PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK), a member of the serine/threonine protein kinase, which regulates the signaling cascades of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal regulated kinase 1/2 (ERK1/2). PBK/TOPK plays a significant role in solar-UV-induced cutaneous basal cell carcinoma (BCC), and targeting PBK/TOPK can be supposed to treat and prevent cutaneous BCC. METHODS: The pathological feature and the expression level of PBK/TOPK in cutaneous BCC tissues of human were studied in clinical samples. SUV-induced the phosphorylation of p38 MAPK and ERK1/2 were demonstrated ex vivo. Moreover, the interaction between Gossypetin and PBK/TOPK were detected by in vitro kinase assay and Microscale thermophoresis (MST) assay. Furthermore, the effect of Gossypetin to solar UV-induced the activity of PBK/TOPK were detected ex vivo and in vivo. RESULTS: The clinical samples showed that the expression levels of PBK/TOPK, phosphor-p38 MAPK and phosphor- ERK1/2 were up-regulated in cutaneous BCC tissues of human. The expression of phosphor-p38 MAPK or phosphor-ERK1/2 increased in a dose and time dependent manner after solar UV treatment in HaCaT cells. MTT cytotoxicity assay results showed that Gossypetin has no effect on HaCaT cells. In vitro kinase assay and MST assay results showed that Gossypetin bound with PBK/TOPK and suppressed PBK/TOPK activity. Ex vivo results showed Gossypetin inhibited solar UV-induced phosphorylation of PBK/TOPK, p38 MAPK, ERK1/2 and H2AX by suppressing PBK/TOPK activity. In vivo test results indicated that Gossypetin suppressed solar UV-induced increase of PBK/TOPK, phosphor-p38 MAPK, phosphor-ERK1/2 and phosphor- H2AX in SKH-1 hairless mice. CONCLUSION: Our data demonstrated that Gossypetin can alleviate solar-UV-induced cutaneous BCC by blocking PBK/TOPK, and Gossypetin could be a remarkable agent for treating solar-UV induced cutaneous basal cell carcinoma.

HMGB1 deficiency reduces H2 O2 -induced oxidative damage in human melanocytes via the Nrf2 pathway.

Oxidative stress leads to melanocyte death and has been implicated in the pathogenesis of vitiligo. The nuclear factor, E2-related factor 2 (Nrf2), is a critical transcription factor in protecting cells from oxidative damage. High-mobility group box 1 (HMGB1) is a chromatin-associated nuclear protein and an extracellular damage-associated molecular pattern molecule. Extracellular HMGB1 released from activated immune cells, necrotic or injured cells, becomes a proinflammatory mediator through binding to cell-surface receptors of responding cells. In this study, we investigated the role of HMGB1 from melanocytes in the response to oxidative stress and the mechanism involved. We showed that HMGB1 is expressed by primary normal human epidermal melanocytes (NHEMs). H2 O2 treatment increased cytoplasmic translocation and extracellular release of HMGB1. HMGB1 knockdown by small interfering RNA (siRNA) led to decreased apoptosis of NHEMs. HMGB1 inhibition enhanced the expression of Nrf2 and its target genes. The expression of Nrf2 and its downstream antioxidant genes was downregulated after the supernatant of H2 O2 -treated NHEMs was added to HMGB1-deficient cells. HMGB1 knockdown by siRNA suppressed the expression of the autophagosome marker, LC3, and enhanced p62 expression. Coimmunoprecipitation with Keap1 showed a reduced Nrf2-Keap1 interaction and an increased p62-Keap1 interaction under oxidative stress. These data demonstrated that external stimuli (eg, oxidative stress) may trigger autocrine HMGB1 translocation and release by melanocytes, suppressing the expression of Nrf2 and downstream antioxidant genes to induce melanocyte apoptosis, and thereby participate in the pathological process of vitiligo.

miR­590­5p inhibits tumor growth in malignant melanoma by suppressing YAP1 expression.

The microRNAs (miRNAs/miRs) involved in the carcinogenesis and progression of malignant melanoma (MM) remain unclear. In the present study, miR­590­5p was identified to be upregulated in MM cells compared with human melanocytes using a reverse transcription­quantitative polymerase chain reaction to screen established oncogenic and tumor suppressor miRNAs. miR­590­5p was demonstrated to inhibit the cell proliferation and tumor growth of MM cells in vitro and in vivo by performing Cell Counting Kit­8 and tumour xenograft assays, respectively. In addition, flowcytometry assays indicated that miR­590­5p induced cell apoptosis and cell cycle arrest at the G1 stage in MM cells. Finally, luciferase assays and western blot analysis results confirmed that the transcriptional regulator Yes­associated protein 1 (YAP1) is upregulated and inversely associated with miR­590­5p expression in MM cells, and is the direct target and functional mediator of miR­590­5p in MM. Altogether these results reveal the functional and mechanistic link between miR­590­5p and YAP1 in the progression of MM. Therefore, miR­590­5p is a potential therapeutic target in MM.

Plum-blossom needling enhanced the effect of photodynamic therapy on basal cell carcinoma.

BACKGROUND/PURPOSE: Basal cell carcinoma (BCC) often occurs on the face of middle and older aged people. Given this particular location, aminolevulinic acid-photodynamic therapy (ALA-PDT) is often applied. Specific measures in PDT treatment should be performed to increase the ALA penetration capability because the limited depth of ALA penetration may not allow for therapy to reach the tumor base. This research aims to explore a method that facilitates ALA penetration. METHODS: Three patients with BCC were subjected to four regular sessions of ALA-PDT every other week. Before the PDT treatment, super pulsed CO2 laser was used to burn a part of the lesions, and plum-blossom needle was then tapped at the lesions for three times. The fresh prepared 20% 5-ALA was coated and kept for 3 h. The lesion was irradiated with red light with 126 J/cm2 at a wavelength of 633 nm and at a rate of 100 mW/cm2 for 30 min. RESULTS: After each session of ALA-PDT, the thickness of BCC gradually decreased. After final session of ALA-PDT, the plaque became a red, painless patch. The lesions were repaired completely, and a left brown patch was left. CONCLUSION: Plum-blossom needle can be effectively applied as adjunctive treatment strategy in the development of ALA-PDT for BCC.

lncRNA-ATB functions as a competing endogenous RNA to promote YAP1 by sponging miR-590-5p in malignant melanoma.

The critical long non­coding RNAs (lncRNAs) involved in the carcinogenesis and progression of malignant melanoma (MM) have not been fully investigated. In the present study, it was identified that lncRNA activated by transforming growth factor­ß (lncRNA­ATB) was upregulated in MM tissues and cells compared with benign nevus cells and human melanocytes, via comparative lncRNA screening from Gene Expression Omnibus datasets and reverse transcription­quantitative polymerase chain reaction analysis. Furthermore, lncRNA­ATB promoted the cell proliferation, cell migration, and cell invasion of MM cells in vitro, and tumor growth in vivo. It was additionally identified that lncRNA­ATB attenuated cell cycle arrest and inhibited cellular apoptosis in MM cells. Finally, it was demonstrated that lncRNA­ATB functions as a competing endogenous RNA (ceRNA) to enhance Yes associated protein 1 expression by competitively sponging microRNA miR­590­5p in MM cells. In conclusion, the present study revealed the expression and roles of lncRNA­ATB in MM, and indicated that lncRNA­ATB functions as a ceRNA to promote MM proliferation and invasion by sponging miR­590­5p.

HMGB1/RAGE axis promotes autophagy and protects keratinocytes from ultraviolet radiation-induced cell death.

BACKGROUND: The primary cause of skin cancer is ultraviolet (UV) light from the sun. Keratinocytes are the predominant cell type in the epidermis and form a barrier against environmental damage, especially from UV light irradiation. Autophagy is a self-digestion mechanism for energy homeostasis at critical times during development and as a response to stress. High-mobility group protein 1 (HMGB1) is a highly conserved nuclear protein that is associated with cell autophagy. OBJECTIVE: We investigated the role of HMGB1 in keratinocytes exposed to UV irradiation and its regulation of keratinocyte autophagy. METHODS: Specimens of UV-exposed human skin were assayed immunohistochemically for HMGB1. HaCaT immortalized human keratinocytes were used to investigate the mechanism of HMGB1 translocation induced by UV irradiation. Levels of cytosolic reactive oxygen species (ROS) were determined by H2DCF assay, apoptosis was assayed by flow cytometry and western-blot after lentivirus-mediated shRNA targeting of HMGB1 in keratinocytes by UV irradiation. Phosphorylated-Erk1/2 expression was assayed by western blotting. RESULTS: HMGB1 and its receptor (receptor for advanced glycation end products, RAGE) were both expressed by HaCaT cells, and HMGB1 was transferred from the nucleus to the cytoplasm after UV irradiation in both HaCaT and human skin keratinocytes. Knockdown of HMGB1 expression by lentivirus-mediated shRNA limited UV-induced autophagy and led to increased apoptosis of HaCaT cells. Pharmacological inhibition of HMGB1 cytoplasmic translocation by agents such as ethyl pyruvate limits starvation-induced autophagy. UV irradiation led to phosphorylation of Erk1/2 in HaCaT cells. Inhibition of RAGE and Erk1/2 limited HaCaT cell autophagy. CONCLUSION: Autocrine HMGB1 modulated HaCaT autophagy via a RAGE/HMGB1/extracellular signal-regulated Erk1/2-dependent pathway to protect keratinocytes from apoptosis during UV irradiation.