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1.
  • Almet, Axel A., et al. (författare)
  • A Roadmap for a Consensus Human Skin Cell Atlas and Single-Cell Data Standardization
  • 2023
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 143:9, s. 1667-1677
  • Forskningsöversikt (refereegranskat)abstract
    • Single-cell technologies have become essential to driving discovery in both basic and translational investigative dermatology. Despite the multitude of available datasets, a central reference atlas of normal human skin, which can serve as a reference resource for skin cell types, cell states, and their molecular signatures, is still lacking. For any such atlas to receive broad acceptance, participation by many investigators during atlas construction is an essential prerequisite. As part of the Human Cell Atlas project, we have assembled a Skin Biological Network to build a consensus Human Skin Cell Atlas and outline a roadmap toward that goal. We define the drivers of skin diversity to be considered when selecting sequencing datasets for the atlas and list practical hurdles during skin sampling that can result in data gaps and impede comprehensive representation and technical considerations for tissue processing and computational analysis, the accounting for which should minimize biases in cell type enrichments and exclusions and decrease batch effects. By outlining our goals for Atlas 1.0, we discuss how it will uncover new aspects of skin biology.
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2.
  • Das Mahapatra, Kunal, et al. (författare)
  • A comprehensive analysis of coding and non-coding transcriptomic changes in cutaneous squamous cell carcinoma
  • 2020
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Cutaneous Squamous Cell Carcinoma (cSCC) is the most common and fastest-increasing cancer with metastatic potential. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are novel regulators of gene expression. To identify mRNAs, lncRNAs and circRNAs, which can be involved in cSCC, RNA-seq was performed on nine cSCCs and seven healthy skin samples. Representative transcripts were validated by NanoString nCounter assays using an extended cohort, which also included samples from pre-cancerous skin lesions (actinic keratosis). 5,352 protein-coding genes, 908 lncRNAs and 55 circular RNAs were identified to be differentially expressed in cSCC. Targets of 519 transcription factors were enriched among differentially expressed genes, 105 of which displayed altered level in cSCCs, including fundamental regulators of skin development (MYC, RELA, ETS1, TP63). Pathways related to cell cycle, apoptosis, inflammation and epidermal differentiation were enriched. In addition to known oncogenic lncRNAs (PVT1, LUCAT1, CASC9), a set of skin-specific lncRNAs were were identified to be dysregulated. A global downregulation of circRNAs was observed in cSCC, and novel skin-enriched circRNAs, circ_IFFO2 and circ_POF1B, were identified and validated. In conclusion, a reference set of coding and non-coding transcripts were identified in cSCC, which may become potential therapeutic targets or biomarkers.
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3.
  • Gastaldi, Cécile, et al. (författare)
  • miR-193b/365a cluster controls progression of epidermal squamous cell carcinoma.
  • 2014
  • Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 35:5, s. 1110-20
  • Tidskriftsartikel (refereegranskat)abstract
    • Incidence of cutaneous squamous cell carcinomas (cSCCs) constantly increases in the Caucasian population. Developing preferentially on precancerous lesions such as actinic keratoses due to chronic sunlight exposure, cSCCs result from the malignant transformation of keratinocytes. Although a resection of the primary tumor is usually curative, a subset of aggressive cSCCs shows a high risk of recurrence and metastases. The characterization of the molecular dysfunctions involved in cSCC development should help to identify new relevant targets against these aggressive cSCCs. In that context, we have used small RNA sequencing to identify 100 microRNAs (miRNAs) whose expression was altered during chemically induced mouse skin tumorigenesis. The decreased expression of the miR-193b/365a cluster during tumor progression suggests a tumor suppressor role. Ectopic expression of these miRNAs in tumor cells indeed inhibited their proliferation, clonogenic potential and migration, which were stimulated in normal keratinocytes when these miRNAs were blocked with antisense oligonucleotides. A combination of in silico predictions and transcriptome analyses identified several target genes of interest. We validated KRAS and MAX as direct targets of miR-193b and miR-365a. Repression of these targets using siRNAs mimicked the effects of miR-193b and miR-365a, suggesting that these genes might mediate, at least in part, the tumor-suppressive action of these miRNAs.
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4.
  • Hoffmann, Thomas K, et al. (författare)
  • A novel mechanism for anti-EGFR antibody action involves chemokine-mediated leukocyte infiltration.
  • 2009
  • Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:11, s. 2589-96
  • Tidskriftsartikel (refereegranskat)abstract
    • Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). Monoclonal antibodies (mAbs) against EGFR are currently used for therapy of recurrent or metastatic disease; however, their mode of action is not completely understood. To investigate the immunological effects of anti-EGFR mAb, we generated a three-dimensional spheroid model of EGFR-expressing SCCHN and used this model to study the effect of anti-EGFR mAb on leukocyte migration toward tumors. Pretreatment with the blocking anti-EGFR mAb EMD 72000, its F(ab')2 fragments or an EGFR tyrosine kinase inhibitor led to substantially increased leukocyte infiltration into EGFR overexpressing tumor spheroids, but not into those with low EGFR expression. Nonblocking anti-EGFR mAb or fibroblast-specific mAb did not affect leukocyte infiltration, suggesting that the observed increase in leukocyte infiltration depends on interference with EGFR activation. Using a human cytokine macroarray, we demonstrated that the blockade of EGFR by anti-EGFR mAb in EGFR-overexpressing SCCHN cells leads to differential expression of several cytokines and chemokines, including the chemokine MCP-1/CCL-2. The significant upregulation of MCP-1/CCL2 on exposure to anti-EGFR mAb was confirmed by quantitative PCR and enzyme-linked immunospot analyses. Moreover, blocking anti-MCP-1 antibody inhibited leukocyte migration toward tumor cells induced by anti-EGFR mAb, pointing to an important role of MCP-1/CCL2 in anti-EGFR mAb-induced leukocyte migration. Our findings demonstrate that anti-EGFR mAb induces leukocyte infiltration to tumor spheroids by upregulating chemokine expression. This novel mechanism for anti-EGFR mAb action may contribute to the antitumor effects of anti-EGFR mAb in vivo.
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5.
  • Li, Chen, et al. (författare)
  • Cutaneous squamous cell carcinoma-derived extracellular vesicles exert an oncogenic role by activating cancer-associated fibroblasts
  • 2023
  • Ingår i: Cell Death Discovery. - : Springer Nature. - 2058-7716. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Cutaneous squamous cell carcinoma (cSCC) is a fast-increasing cancer with metastatic potential. Extracellular vesicles (EVs) are small membrane-bound vesicles that play important roles in intercellular communication, particularly in the tumor microenvironment (TME). Here we report that cSCC cells secrete an increased number of EVs relative to normal human epidermal keratinocytes (NHEKs) and that interfering with the capacity of cSCC to secrete EVs inhibits tumor growth in vivo in a xenograft model of human cSCC. Transcriptome analysis of tumor xenografts by RNA-sequencing enabling the simultaneous quantification of both the human and the mouse transcripts revealed that impaired EV-production of cSCC cells prominently altered the phenotype of stromal cells, in particular genes related to extracellular matrix (ECM)-formation and epithelial-mesenchymal transition (EMT). In line with these results, co-culturing of human dermal fibroblasts (HDFs) with cSCC cells, but not with normal keratinocytes in vitro resulted in acquisition of cancer-associated fibroblast (CAF) phenotype. Interestingly, EVs derived from metastatic cSCC cells, but not primary cSCCs or NHEKs, were efficient in converting HDFs to CAFs. Multiplex bead-based flow cytometry assay and mass-spectrometry (MS)-based proteomic analyses revealed the heterogenous cargo of cSCC-derived EVs and that especially EVs derived from metastatic cSCCs carry proteins associated with EV-biogenesis, EMT, and cell migration. Mechanistically, EVs from metastatic cSCC cells result in the activation of TGFβ signaling in HDFs. Altogether, our study suggests that cSCC-derived EVs mediate cancer-stroma communication, in particular the conversion of fibroblasts to CAFs, which eventually contribute to cSCC progression.
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6.
  • Li, Chen, et al. (författare)
  • Long non-coding RNA PVT1 is overexpressed in cutaneous squamous cell carcinoma and exon 2 is critical for its oncogenicity : Long non-coding RNA PVT1 in cutaneous squamous cell carcinoma
  • Ingår i: British Journal of Dermatology. - 0007-0963 .- 1365-2133.
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundCutaneous squamous cell carcinoma (cSCC) is one of the most common and fastest increasing forms of cancer worldwide with metastatic potential. Long non-coding RNAs (lncRNAs) are a group of RNA-molecules with essential regulatory functions for both physiological and pathological processes.ObjectivesTo investigate the function and mode of action of lncRNA plasmacytoma variant translocation 1 (PVT1) in cSCC.MethodsThe expression level of PVT1 was quantified in normal skin, premalignant skin lesion actinic keratosis (AK) and cSCCs by qRT-PCR and single molecule in situ hybridization. The function of PVT1 in cSCC was investigated both in vivo (tumour xenograft) and in vitro (competitive cell growth assay, EdU-incorporation assay, colony formation assay and tumour spheroid formation assay) by CRISPR-Cas9-mediated knockout of the entire PVT1 locus or PVT1 exon 2, and by locked nucleic acid (LNA) GapmeR-mediated PVT1-knockdown. RNA-seq-analysis was conducted to identify genes and processes regulated by PVT1.ResultsWe identified PVT1 as a lncRNA upregulated in cutaneous squamous cell carcinoma in situ (cSCCIS) and cSCC and associated with oncogenic phenotype of cSCC. The increased expression of PVT1 in cSCC was regulated by MYC. Both CRISPR-Cas9-deletion of the entire PVT1 locus and LNA GapmeR-mediated knockdown of PVT1-transcript impaired the malignant behaviour of cSCC cells which suggested that PVT1 is an oncogenic transcript in cSCC. Furthermore, knockout of PVT1 exon 2 inhibited cSCC tumour growth both in vivo and in vitro demonstrating that exon 2 is a critical element for the oncogenic role of PVT1. Mechanistically, we showed that PVT1 was localized in the cell nucleus and acted as a suppressor of cellular senescence by inhibiting CDKN1A expression and preventing cell cycle arrest.ConclusionsOur study reveals a previously unrecognized role for exon 2 of PVT1 in its oncogenic role and that PVT1 suppresses cellular senescence in cSCC. PVT1 may be a biomarker and therapeutic target in cSCC.
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7.
  • Li, Chen, et al. (författare)
  • Long noncoding RNA plasmacytoma variant translocation 1 is overexpressed in cutaneous squamous cell carcinoma and exon 2 is critical for its oncogenicity
  • 2023
  • Ingår i: British Journal of Dermatology. - : Oxford University Press. - 0007-0963 .- 1365-2133. ; 190:3, s. 415-426
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundCutaneous squamous cell carcinoma (cSCC) is one of the most common and fastest increasing forms of cancer worldwide with metastatic potential. Long noncoding RNAs (lncRNAs) are a group of RNA molecules with essential regulatory functions in both physiological and pathological processes.ObjectivesTo investigate the function and mode of action of lncRNA plasmacytoma variant translocation 1 (PVT1) in cSCC.MethodsQuantitative reverse transcriptase polymerase chain reaction and single-molecule in situ hybridization were used to quantify the expression level of PVT1 in normal skin, premalignant skin lesions, actinic keratosis (AK) and primary and metastatic cSCCs. The function of PVT1 in cSCC was investigated both in vivo (tumour xenografts) and in vitro (competitive cell growth assay, 5-ethynyl-2′-deoxyuridine incorporation assay, colony formation assay and tumour spheroid formation assay) upon CRISPR-Cas9-mediated knockout of the entire PVT1 locus, the knockout of exon 2 of PVT1, and locked nucleic acid (LNA) gapmer-mediated PVT1 knockdown. RNA sequencing analysis was conducted to identify genes and processes regulated by PVT1.ResultsWe identified PVT1 as a lncRNA upregulated in cSCC in situ and cSCC, associated with the malignant phenotype of cSCC. We showed that the expression of PVT1 in cSCC was regulated by MYC. Both CRISPR-Cas9 deletion of the entire PVT1 locus and LNA gapmer-mediated knockdown of PVT1 transcript impaired the malignant behaviour of cSCC cells, suggesting that PVT1 is an oncogenic transcript in cSCC. Furthermore, knockout of PVT1 exon 2 inhibited cSCC tumour growth both in vivo and in vitro, demonstrating that exon 2 is a critical element for the oncogenic role of PVT1. Mechanistically, we showed that PVT1 was localized in the cell nucleus and its deletion resulted in cellular senescence, increased cyclin-dependent kinase inhibitor 1 (p21/CDKN1A) expression and cell cycle arrest.ConclusionsOur study revealed a previously unrecognized role for exon 2 of PVT1 in its oncogenic role and that PVT1 suppresses cellular senescence in cSCC. PVT1 may be a potential biomarker and therapeutic target in cSCC.
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8.
  • Li, Chen, et al. (författare)
  • PVT1 regulates the nuclear export of polyadenylated RNAs through interacting with TREX complex
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • PVT1 is known to be involved in the development and progression of several types of cancer. In this study, we investigated the molecular mechanism by which PVT1 contributes to cutaneous squamous cell carcinoma (cSCC) promotion. RNA-seq data obtained from PVT1 exon2 knockout (PVT1 E2KO) cells suggested that PVT1 exerts functions in regulating RNA processing. Comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-ms) and RNA immunoprecipitation (RIP) assays indicated that PVT1 interacts with the subunits (UAP56, URH49 and Aly) of the TRanscription and EXport (TREX) complex, an evolutionarily conserved complex coupling mRNA biogenesis from transcription to nucleus export. Single molecule fluorescence in situ hybridization revealed that the exon2 of PVT1 and UAP56 are responsible for the nuclear localization of PVT1 transcripts as demonstrated by diffuse cytoplasmic localization of PVT1 transcripts in both PVT1 E2KO and UAP56 knockout (UAP56KO) cells. Notably, we show that PVT1 is indispensable for the export of poly (A)+ RNAs from cell nucleus to cytoplasm and that poly (A)+ RNAs are accumulated in the nuclear speckles of PVT1 E2KO cells. PVT1 exon 2-deletion also resulted in cytokinesis failure which is characterized by multinucleated cell formation. One of the nuclear accumulated RNAs in PVT1 exon 2-deleted cells is Lamin B1 mRNA, whose reduction is associated with cellular senescence. Impaired export of Lamin B1 mRNA to cytoplasm decreased the expression level of Lamin B1 protein in PVT1 E2KO cells and promoted the progress of cellular senescence. Taken together, our study uncovered a previously unknown role of PVT1 in the nuclear export of poly (A)+ RNAs.
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9.
  • Li, Dongqing, et al. (författare)
  • MicroRNA-132 enhances transition from inflammation to proliferation during wound healing.
  • 2015
  • Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:8, s. 3008-26
  • Tidskriftsartikel (refereegranskat)abstract
    • Wound healing is a complex process that is characterized by an initial inflammatory phase followed by a proliferative phase. This transition is a critical regulatory point; however, the factors that mediate this process are not fully understood. Here, we evaluated microRNAs (miRs) in skin wound healing and characterized the dynamic change of the miRNome in human skin wounds. miR-132 was highly upregulated during the inflammatory phase of wound repair, predominantly expressed in epidermal keratinocytes, and peaked in the subsequent proliferative phase. TGF-β1 and TGF-β2 induced miR-132 expression in keratinocytes, and transcriptome analysis of these cells revealed that miR-132 regulates a large number of immune response- and cell cycle-related genes. In keratinocytes, miR-132 decreased the production of chemokines and the capability to attract leukocytes by suppressing the NF-κB pathway. Conversely, miR-132 increased activity of the STAT3 and ERK pathways, thereby promoting keratinocyte growth. Silencing of the miR-132 target heparin-binding EGF-like growth factor (HB-EGF) phenocopied miR-132 overexpression in keratinocytes. Using mouse and human ex vivo wound models, we found that miR-132 blockade delayed healing, which was accompanied by severe inflammation and deficient keratinocyte proliferation. Together, our results indicate that miR-132 is a critical regulator of skin wound healing that facilitates the transition from the inflammatory to the proliferative phase.
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10.
  • Li, Dongqing, et al. (författare)
  • MicroRNA-31 Promotes Skin Wound Healing by Enhancing Keratinocyte Proliferation and Migration.
  • 2015
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 135:6, s. 1676-1685
  • Tidskriftsartikel (refereegranskat)abstract
    • Wound healing is a basic biological process restoring the integrity of the skin. The role of microRNAs during this process remains largely unexplored. By using an in vivo human skin wound healing model, we show here that the expression of miR-31 is gradually upregulated in wound edge keratinocytes in the inflammatory (1 day after injury) through the proliferative phase (7 days after injury) in comparison with intact skin. In human primary keratinocytes, overexpression of miR-31 promoted cell proliferation and migration, whereas inhibition of miR-31 had the opposite effects. Moreover, we identified epithelial membrane protein 1 (EMP-1) as a direct target of miR-31 in keratinocytes. The expression of EMP-1 in the skin was negatively correlated with the level of miR-31 during wound healing. Silencing of EMP-1 mimicked the effects of overexpression of miR-31 on keratinocyte proliferation and migration, indicating that EMP-1 is a critical target mediating the functions of miR-31 in keratinocytes. Finally, we demonstrated that transforming growth factor-β2, which is highly expressed in skin wounds, upregulated miR-31 expression in keratinocytes. Collectively, we identify miR-31 as a key regulator for promoting keratinocyte proliferation and migration during wound healing.
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11.
  • Li, Dongqing, et al. (författare)
  • miR-19a/b and miR-20a promote wound healing by regulating the inflammatory response of keratinocytes
  • 2021
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 141:3, s. 659-671
  • Tidskriftsartikel (refereegranskat)abstract
    • Persistent and impaired inflammation impedes tissue healing and is characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. Here we show that in human wound-edge keratinocytes, the expression of miR-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17∼92 cluster, is upregulated during wound repair. However, their levels are lower in chronic ulcers than acute wounds at the proliferative phase. Conditional knockout of miR-17∼92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound-edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17∼92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-κB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines/cytokines by keratinocytes. Thus, as crucial regulators of wound inflammation, lack of miR-19a/b and miR-20a may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes.
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12.
  • Li, X, et al. (författare)
  • MicroRNA-132 promotes fibroblast migration via regulating RAS p21 protein activator 1 in skin wound healing
  • 2017
  • Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 7797-
  • Tidskriftsartikel (refereegranskat)abstract
    • MicroRNA (miR)-132 has been identified as a top up-regulated miRNA during skin wound healing and its inhibition impairs wound repair. In a human in vivo surgical wound model, we showed that miR-132 was induced in epidermal as well as in dermal wound–edge compartments during healing. Moreover, in a panel of cells isolated from human skin wounds, miR-132 was found highly expressed in human dermal fibroblasts (HDFs). In HDFs, miR-132 expression was upregulated by TGF-β1. By overexpression or inhibition of miR-132, we showed that miR-132 promoted HDF migration. Mechanistically, global transcriptome analysis revealed that RAS signaling pathway was regulated by miR-132 in HDFs. We found that RAS p21 protein activator 1 (RASA1), a known target of miR-132, was downregulated in HDFs upon miR-132 overexpression. Silencing of RASA1 phenocopied the pro-migratory effect of miR-132. Collectively, our study reveals an important role for miR-132 in HDFs during wound healing and indicates a therapeutic potential of miR-132 in hard-to-heal skin wounds.
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13.
  • Li, Xi, et al. (författare)
  • MicroRNA-132 with Therapeutic Potential in Chronic Wounds.
  • 2017
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 137:12, s. 2630-2638
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic wounds represent a major and rising health and economic burden worldwide. There is a continued search toward more effective wound therapy. We found significantly reduced microRNA-132 (miR-132) expression in human diabetic ulcers compared with normal skin wounds and also in skin wounds of leptin receptor-deficient (db/db) diabetic mice compared with wild-type mice. Local replenishment of miR-132 in the wounds of db/db mice accelerated wound closure effectively, which was accompanied by increased proliferation of wound edge keratinocytes and reduced inflammation. The pro-healing effect of miR-132 was further supported by global transcriptome analysis, which showed that several inflammation-related signaling pathways (e.g., NF-κB, NOD-like receptor, toll-like receptor, and tumor necrosis factor signaling pathways) were the top ones regulated by miR-132 in vivo. Moreover, we topically applied liposome-formulated miR-132 mimics mixed with pluronic F-127 gel on human ex vivo skin wounds, which promoted re-epithelialization. Together, our study showed the therapeutic potential of miR-132 in chronic wounds, which warrants further evaluation in controlled clinical trials.
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14.
  • Lohcharoenkal, Warangkana, et al. (författare)
  • Genome-Wide Screen for MicroRNAs Reveals a Role for miR-203 in Melanoma Metastasis.
  • 2018
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 138:4, s. 882-892
  • Tidskriftsartikel (refereegranskat)abstract
    • Melanoma is one of the deadliest human cancers with limited therapeutic options. MicroRNAs are a class of short noncoding RNAs regulating gene expression at the post-transcriptional level. To identify important miRNAs in melanoma, we compared the miRNome of primary and metastatic melanomas in The Cancer Genome Atlas dataset and found lower miR-203 abundance in metastatic melanoma. Lower level of miR-203 was associated with poor overall survival in metastatic disease. We found that the methylation levels of several CpGs in the MIR203 promoter negatively correlated with miR-203 expression and that treatment with the demethylating agent 5-aza-2-deoxycytidine induced miR-203 expression, which was associated with demethylation of the promoter CpGs, in melanoma cell lines. In vitro, there was a decreased expression of miR-203 in melanoma cell lines in comparison with primary melanocytes. Ectopic overexpression of miR-203 suppressed cell motility, colony formation, and sphere formation as well as the angiogenesis-inducing capacity of melanoma cells. In vivo, miR-203 inhibited xenograft tumor growth and reduced lymph node and lung metastasis. SLUG was shown as a target of miR-203, and knockdown of SLUG recapitulated the effects of miR-203, whereas its restoration was able to reverse the miR-203-mediated suppression of cell motility. These results establish a role for miR-203 as a tumor suppressor in melanoma which suppresses both early and late steps of metastasis. Hence, restoration of miR-203 has therapeutic potential in melanoma.
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15.
  • Lohcharoenkal, Warangkana, et al. (författare)
  • MicroRNA-203 Inversely Correlates with Differentiation Grade, Targets c-MYC, and Functions as a Tumor Suppressor in cSCC.
  • 2016
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 136:12, s. 2485-2494
  • Tidskriftsartikel (refereegranskat)abstract
    • Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer and a leading cause of cancer mortality among solid organ transplant recipients. MicroRNAs (miR) are short RNAs that regulate gene expression and cellular functions. Here, we show a negative correlation between miR-203 expression and the differentiation grade of cSCC. Functionally, miR-203 suppressed cell proliferation, cell motility, and the angiogenesis-inducing capacity of cSCC cells in vitro and reduced xenograft tumor volume and angiogenesis in vivo. Transcriptomic analysis of cSCC cells with ectopic overexpression of miR-203 showed dramatic changes in gene networks related to cell cycle and proliferation. Transcription factor enrichment analysis identified c-MYC as a hub of miR-203-induced transcriptomic changes in squamous cell carcinoma. We identified c-MYC as a direct target of miR-203. Overexpression of c-MYC in rescue experiments reversed miR-203-induced growth arrest in cSCC, which highlights the importance of c-MYC within the miR-203-regulated gene network. Together, miR-203 acts as a tumor suppressor in cSCC, and its low expression can be a marker for poorly differentiated tumors. Restoration of miR-203 expression may provide a therapeutic benefit, particularly in poorly differentiated cSCC.
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16.
  • Luo, Longlong, et al. (författare)
  • The Long Noncoding RNA LINC00958 Is Induced in Psoriasis Epidermis and Modulates Epidermal Proliferation
  • 2023
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 143:6, s. 999-1010
  • Tidskriftsartikel (refereegranskat)abstract
    • Psoriasis is a common, immune-mediated skin disease characterized by epidermal hyperproliferation and chronic skin inflammation. Long noncoding RNAs are >200 nucleotide-long transcripts that possess important regulatory functions. To date, little is known about the contribution of long noncoding RNAs to psoriasis. In this study, we identify LINC00958 as a long noncoding RNA overexpressed in keratinocytes (KCs) from psoriasis skin lesions, in a transcriptomic screen performed on KCs sorted from psoriasis and healthy skin. Increased levels of LINC00958 in psoriasis KCs were confirmed by RT-qPCR and single-molecule in situ hybridization. Confocal microscopy and analysis of subcellular fractions showed that LINC00958 is mainly localized in the cytoplasm of KCs. IL-17A, a key psoriasis cytokine, induced LINC00958 in KCs through C/EBP-β and the p38 pathway. The inhibition of LINC00958 led to decreased proliferation as measured by Ki-67 expression, live cell analysis imaging, and 5-ethynyl-2-deoxyuridine assays. Transcriptomic analysis of LINC00958-depleted KCs revealed enrichment of proliferation- and cell cycle‒related genes among differentially expressed transcripts. Moreover, LINC00958 depletion led to decreased basal and IL-17A‒induced phosphorylation of p38. Furthermore, IL-17A‒induced KC proliferation was counteracted by the inhibition of LINC00958. In summary, our data support a role for the IL-17A‒induced long noncoding RNA, LINC00958, in the pathological circuits of psoriasis by reinforcing IL-17A‒induced epidermal hyperproliferation.
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17.
  • Meisgen, Florian, et al. (författare)
  • Activation of toll-like receptors alters the microRNA expression profile of keratinocytes.
  • 2014
  • Ingår i: Experimental dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 23:4, s. 281-3
  • Tidskriftsartikel (refereegranskat)abstract
    • Keratinocytes recognize invading pathogens by various receptors, among them Toll-like receptors (TLRs), and provide the first line of defense in skin immunity. The role of microRNAs in this important defense mechanism has not been explored yet. Our aim was to identify microRNAs involved in the innate immune response of keratinocytes. MicroRNA expression profiling revealed that the TLR2 ligand zymosan, the TLR3 ligand poly(I:C) or the TLR5 ligand flagellin significantly altered the microRNA expression in keratinocytes. The regulation of microRNAs was concentration-dependent and it could be neutralized by siRNAs specific for TLR2, TLR3 and TLR5, respectively, confirming the specificity of the TLR response. Interestingly, one microRNA, miR-146a, was strongly induced by all studied TLR ligands, while other microRNAs were regulated in a TLR- or time point-specific manner. These findings suggest an important role for microRNAs in the innate immune response of keratinocytes and provide a basis for further investigations.
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18.
  • Meisgen, Florian, et al. (författare)
  • MiR-146a negatively regulates TLR2-induced inflammatory responses in keratinocytes.
  • 2014
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 134:7, s. 1931-1940
  • Tidskriftsartikel (refereegranskat)abstract
    • Keratinocytes represent the first line of defense against pathogens in the skin and have important roles in initiating and regulating inflammation during infection and autoimmunity. Here we investigated the role of miR-146a in the regulation of the innate immune response of keratinocytes. Toll-like receptor 2 (TLR2) stimulation of primary human keratinocytes resulted in an NF-κB- and mitogen-activated protein kinase-dependent upregulation of miR-146a expression, which was surprisingly long lasting, contrasting with the rapid and transient induction of inflammatory mediators. Overexpression of miR-146a significantly suppressed the production of IL-8, CCL20, and tumor necrosis factor-α, which functionally suppressed the chemotactic attraction of neutrophils by keratinocytes. Inhibition of endogenous miR-146a induced the production of inflammatory mediators even in nonstimulated keratinocytes, and potentiated the effect of TLR2 stimulation. Transcriptomic profiling revealed that miR-146a suppresses the expression of a large number of immune-related genes in keratinocytes. MiR-146a downregulated interleukin-1 receptor-associated kinase 1 and TNF receptor-associated factor 6, two key adapter molecules downstream of TLR signaling, and suppressed NF-κB promoter-binding activity as shown by promoter luciferase experiments. Together, these data identify miR-146a as a regulatory element in keratinocyte innate immunity, which prevents the production of inflammatory mediators under homeostatic conditions and serves as a potent negative feedback regulator after TLR2 stimulation.
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19.
  • Meisgen, Florian, et al. (författare)
  • MiR-21 is up-regulated in psoriasis and suppresses T cell apoptosis.
  • 2012
  • Ingår i: Experimental dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 21:4, s. 312-4
  • Tidskriftsartikel (refereegranskat)abstract
    • MicroRNAs are short non-coding RNAs that regulate gene expression. Previously, in a genome-wide screen, we found deregulation of microRNA expression in psoriasis skin. MicroRNA-21 (miR-21) is one of the microRNAs significantly up-regulated in psoriasis skin lesions. To identify the cell type responsible for the increased miR-21 level, we compared expression of miR-21 in epidermal cells and dermal T cells between psoriasis and healthy skin and found elevated levels of miR-21 in psoriasis in both cell types. In cultured T cells, expression of miR-21 increased markedly upon activation. To explore the function of miR-21 in primary human T helper cells, we inhibited miR-21 using a tiny seed-targeting LNA-anti-miR. Specific inhibition of miR-21 increased the apoptosis rate of activated T cells. Our results suggest that miR-21 suppresses apoptosis in activated T cells, and thus, overexpression of miR-21 may contribute to T cell-derived psoriatic skin inflammation.
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20.
  • Pasquali, Lorenzo, et al. (författare)
  • The Keratinocyte Transcriptome in Psoriasis : Pathways Related to Immune Responses, Cell Cycle and Keratinization.
  • 2019
  • Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 99:2, s. 196-205
  • Tidskriftsartikel (refereegranskat)abstract
    • Psoriasis is a common immune-mediated disease resulting from altered cross-talk between keratinocytes and immune cells. Previous transcriptomic studies have identified thousands of deregulated genes in psoriasis skin; however, the transcriptomic changes confined to the epidermal compartment remained poorly characterized. The aim of this study was to characterize the transcriptomic landscape of psoriatic keratinocytes, using sorted CD45neg epidermal cells. Genes with functions in innate immunity, type I interferon response, cell cycle and keratinization were enriched among deregulated genes in psoriatic keratinocytes. Gene set enrichment analysis indicated the dominance of interleukin (IL)-22/IL-17A signatures in the epidermal psoriasis-signature. A set of deregulated genes overlapped with psoriasis-associated genetic regions, suggesting that genetic variations affecting gene expression in keratinocytes contribute to susceptibility to psoriasis. Several psoriasis-susceptibility genes, which were previously believed to be expressed preferentially or exclusively in immune cells, were identified as having altered expression in psoriatic keratinocytes. These results highlight the role of keratinocytes in the pathogenesis of psoriasis, and indicate that both genetic factors and an inflammatory microenvironment contribute to epidermal alterations in psoriasis.
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21.
  • Sahlén, Pelin, et al. (författare)
  • Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis– and psoriasis-associated genes
  • 2020
  • Ingår i: Journal of Allergy and Clinical Immunology. - : Mosby Inc.. - 0091-6749 .- 1097-6825.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear. Objective: We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate. Methods: We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies. Results: We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis. Conclusions: Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.
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22.
  • Shimokawa, Takashi, et al. (författare)
  • RNA editing of the GLI1 transcription factor modulates the output of Hedgehog signaling.
  • 2013
  • Ingår i: RNA Biology. - : Informa UK Limited. - 1547-6286 .- 1555-8584. ; 10:2, s. 321-33
  • Tidskriftsartikel (refereegranskat)abstract
    • The Hedgehog (HH) signaling pathway has important roles in tumorigenesis and in embryonal patterning. The Glioma-associated oncogene 1 (GLI1) is a key molecule in HH signaling, acting as a transcriptional effector and, moreover, is considered to be a potential therapeutic target for several types of cancer. To extend our previous focus on the implications of alternative splicing for HH signal transduction, we now report on an additional post-transcriptional mechanism with an impact on GLI1 activity, namely RNA editing. The GLI1 mRNA is highly edited at nucleotide 2179 by adenosine deamination in normal cerebellum, but the extent of this modification is reduced in cell lines from the cerebellar tumor medulloblastoma. Additionally, basal cell carcinoma tumor samples exhibit decreased GLI1 editing compared with normal skin. Interestingly, knocking down of either ADAR1 or ADAR2 reduces RNA editing of GLI1. This adenosine to inosine substitution leads to a change from Arginine to Glycine at position 701 that influences not only GLI1 transcriptional activity, but also GLI1-dependent cellular proliferation. Specifically, the edited GLI1, GLI1-701G, has a higher capacity to activate most of the transcriptional targets tested and is less susceptible to inhibition by the negative regulator of HH signaling suppressor of fused. However, the Dyrk1a kinase, implicated in cellular proliferation, is more effective in increasing the transcriptional activity of the non-edited GLI1. Finally, introduction of GLI1-701G into medulloblastoma cells confers a smaller increase in cellular growth relative to GLI1. In conclusion, our findings indicate that RNA editing of GLI1 is a regulatory mechanism that modulates the output of the HH signaling pathway.
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23.
  • Sonkoly, Enikö, et al. (författare)
  • Guselkumab in Patients with Scalp Psoriasis : A post hoc Analysis of the VOYAGE 2 Phase III Randomized Clinical Trial
  • 2024
  • Ingår i: Acta Dermato-Venereologica. - : Acta Dermato-Venereologica. - 0001-5555 .- 1651-2057. ; 104
  • Tidskriftsartikel (refereegranskat)abstract
    • Scalp psoriasis affects approximately 80% of patients with psoriasis and can negatively impact their quality of life. This post hoc analysis of the VOYAGE 2 Phase III randomized clinical trial evaluated scalp response to guselkumab treatment and its association with skin response and patient -reported outcomes. The study included patients with moderate -to -severe plaque psoriasis and baseline scalp psoriasis who were initially randomized to receive guselkumab. Patients were divided into 3 groups based on their achievement of a Psoriasis Area and Severity Index 90 response at week 28: responder continuation, non -responder continuation and responder withdrawal. In all 3 groups, mean Psoriasis Area and Severity Index head and scalpspecific Investigator's Global Assessment scores improved through week 28. In the responder withdrawal group, these scores worsened after treatment withdrawal at week 28, but remained stable through week 48 in both continuation groups. Trends in Dermatology Life Quality Index and Psoriasis Symptoms and Signs Diary itch scores mirrored those of mean scalp -specific Investigator's Global Assessment scores through week 48. Within -subject correlations were 0.83 between scalp -specific Investigator's Global Assessment and Psoriasis Area and Severity Index head scores and 0.78 between scalp -specific Investigator's Global Assessment and Psoriasis Symptoms and Signs Diary itch scores. Through week 252, Psoriasis Area and Severity Index head scores remained stable in the responder continuation group, improved in the non -responder continuation group and rapidly improved by week 84 in the responder withdrawal group after retreatment.
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24.
  • Sonkoly, Enikö, et al. (författare)
  • MicroRNAs : novel regulators involved in the pathogenesis of psoriasis?
  • 2007
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 2:7
  • Tidskriftsartikel (refereegranskat)abstract
    • MicroRNAs are a recently discovered class of posttranscriptional regulators of gene expression with critical functions in health and disease. Psoriasis is the most prevalent chronic inflammatory skin disease in adults, with a substantial negative impact on the patients' quality of life. Here we show for the first time that psoriasis-affected skin has a specific microRNA expression profile when compared with healthy human skin or with another chronic inflammatory skin disease, atopic eczema. Among the psoriasis-specific microRNAs, we identified leukocyte-derived microRNAs and one keratinocyte-derived microRNA, miR-203. In a panel of 21 different human organs and tissues, miR-203 showed a highly skin-specific expression profile. Among the cellular constituents of the skin, it was exclusively expressed by keratinocytes. The up-regulation of miR-203 in psoriatic plaques was concurrent with the down-regulation of an evolutionary conserved target of miR-203, suppressor of cytokine signaling 3 (SOCS-3), which is involved in inflammatory responses and keratinocyte functions. Our results suggest that microRNA deregulation is involved in the pathogenesis of psoriasis and contributes to the dysfunction of the cross talk between resident and infiltrating cells. Taken together, a new layer of regulatory mechanisms is involved in the pathogenesis of chronic inflammatory skin diseases.
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25.
  • Sonkoly, Enikö, et al. (författare)
  • MicroRNAs and immunity : novel players in the regulation of normal immune function and inflammation.
  • 2008
  • Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1044-579X .- 1096-3650. ; 18:2, s. 131-40
  • Tidskriftsartikel (refereegranskat)abstract
    • The discovery of microRNAs (miRNAs) is one of the major scientific breakthroughs in recent years and has revolutionized the way we look at gene regulation. Although we are still at a very early stage in understanding their impact on immunity, miRNAs are changing the way we think about the development of the immune system and regulation of immune functions. MiRNAs are implicated in establishing and maintaining the cell fate of immune cells (e.g. miR-181a and miR-223), and they are involved in innate immunity by regulating Toll-like receptor signaling and ensuing cytokine response (e.g. miR-146). Moreover, miRNAs regulate central elements of the adaptive immune response such as antigen presentation (e.g. miR-155) and T cell receptor signaling (miR-181a). Recent evidence showing altered miRNA expression in chronic inflammatory diseases (e.g. miR-203 and miR-146) suggests their involvement in immune-mediated diseases. Furthermore, miRNAs have been implicated in viral immune escape and anti-viral defense (e.g. miR-196). In this review, we will summarize the latest findings about the role of miRNAs in the development of the immune system and regulation of immune functions and inflammation.
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26.
  • Sonkoly, Enikö, et al. (författare)
  • microRNAs in inflammation.
  • 2009
  • Ingår i: International Reviews of Immunology. - : Informa UK Limited. - 0883-0185 .- 1563-5244. ; 28:6, s. 535-61
  • Tidskriftsartikel (refereegranskat)abstract
    • microRNAs are small noncoding RNAs that regulate protein-coding genes via posttranscriptional repression. Most protein-coding genes are subjected to microRNA-mediated regulation, making the potential effect of these small molecules on regulatory networks enormous. Recent research has implicated miRNAs in the regulation of innate and adaptive immune responses as well as inflammatory networks in various cell and tissue types. In this review, we summarize the current knowledge about miRNAs in immunity and inflammation, focusing on the recent results on miRNAs involved in the regulation of immune responses and inflammatory diseases.
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27.
  • Sonkoly, Enikö, et al. (författare)
  • MicroRNAs in inflammation and response to injuries induced by environmental pollution.
  • 2011
  • Ingår i: Mutation research. - : Elsevier BV. - 0027-5107 .- 1873-135X. ; 717:1-2, s. 46-53
  • Tidskriftsartikel (refereegranskat)abstract
    • MicroRNAs (miRNAs) are small noncoding RNAs that regulate basic biological processes by posttranscriptional suppression of their target genes. Altered miRNA expression may lead to widespread gene expression changes and has been implicated in pathophysiological processes such as cancer and inflammation. In this review, we summarize the present knowledge about the role of miRNAs in inflammation and in the response to environmental agents and pollutants, such as cigarette smoke, ethanol, carcinogenic chemicals such as benzo(a)pyrene (BaP) and dioxin, and UV radiation.
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28.
  • Sonkoly, Enikö, et al. (författare)
  • MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4.
  • 2010
  • Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 126:3, s. 581-9.e1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs that suppress gene expression at the posttranscriptional level. Atopic dermatitis is a common chronic inflammatory skin disease characterized by the presence of activated T cells within the skin.OBJECTIVE: We sought to explore the role of miRNAs in the pathogenesis of atopic dermatitis.METHODS: Global miRNA expression in healthy and lesional skin of patients with atopic dermatitis was compared by using TaqMan MicroRNA Low Density Arrays. miR-155 expression in tissues and cells was quantified by means of quantitative real-time PCR. The cellular localization of miR-155 was analyzed by means of in situ hybridization. The regulation of cytotoxic T lymphocyte-associated antigen (CTLA-4) by miR-155 was investigated by using luciferase reporter assays and flow cytometry. CTLA-4 expression and functional assays were performed on T(H) cells overexpressing miR-155.RESULTS: miR-155 was one of the highest-ranked upregulated miRNAs in patients with atopic dermatitis. In the skin miR-155 was predominantly expressed in infiltrating immune cells. miR-155 was upregulated during T-cell differentiation/activation and was markedly induced by T-cell activators in PBMCs in vitro and by superantigens and allergens in the skin in vivo. CTLA-4, an important negative regulator of T-cell activation, was identified as a direct target of miR-155. Overexpression of miR-155 in T(H) cells resulted in decreased CTLA-4 levels accompanied by an increased proliferative response.CONCLUSION: miR-155 is significantly overexpressed in patients with atopic dermatitis and might contribute to chronic skin inflammation by increasing the proliferative response of T(H) cells through the downregulation of CTLA-4.
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29.
  • Sonkoly, Enikö, et al. (författare)
  • Protein kinase C-dependent upregulation of miR-203 induces the differentiation of human keratinocytes
  • 2010
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 130:1, s. 124-134
  • Tidskriftsartikel (refereegranskat)abstract
    • Terminal differentiation of keratinocytes is a multistep process that requires a coordinated program of gene expression. We aimed to explore the possible involvement of a previously unreported class of non-coding RNA genes, microRNAs (miRNAs) in keratinocyte differentiation by using miRNA expression profiling. Out of 365 miRNAs tested, 7 showed significant change between keratinocytes cultured in low or high calcium concentration. The highest-ranked upregulated gene was miR-203, whose expression was significantly upregulated in response to calcium and other inducers of keratinocyte differentiation such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and vitamin D(3). Differentiation-induced upregulation of miR-203 expression was blocked by treatment with specific inhibitors of protein kinase C (PKC), GF109203X, and Ro31-8220. Moreover, our results showed that the activator protein-1 (AP-1) proteins c-Jun and JunB regulate miR-203 expression in keratinocytes. In contrast to inducers of keratinocyte differentiation, epidermal growth factor and keratinocyte growth factor suppressed miR-203 expression in keratinocytes below the basal level. Overexpression of miR-203 in keratinocytes resulted in enhanced differentiation, whereas inhibition of miR-203 suppressed calcium-induced terminal differentiation as judged by involucrin expression. These results suggest that upregulation of miR-203 in human keratinocytes is required for their differentiation and is dependent on the activation of the PKC/AP-1 pathway.
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30.
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31.
  • Srivastava, Ankit, et al. (författare)
  • Cross-talk between IFN-γ and TWEAK through miR-149 amplifies skin inflammation in psoriasis
  • 2021
  • Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 147:6, s. 2225-2235
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Psoriasis is a chronic inflammatory skin disease with disturbed interplay between immune cells and keratinocytes. A strong IFN-γ signature is characteristic for psoriasis skin, but the role of IFN-γ has been elusive. MicroRNAs are short RNAs regulating gene expression.OBJECTIVE: Our aim was to investigate the role of miR-149 in psoriasis and in the inflammatory responses of keratinocytes.METHODS: miR-149 expression was measured by quantitative RT-PCR in keratinocytes isolated from healthy skin and lesional and nonlesional psoriasis skin. Synthetic miR-149 was injected intradermally into the back skin of mice, and imiquimod was applied to induce psoriasis-like skin inflammation, which was then evaluated at the morphologic, histologic, and molecular levels. miR-149 was transiently overexpressed or inhibited in keratinocytes in combination with IFN-γ- and/or TNF-related weak inducer of apoptosis (TWEAK)-treatment.RESULTS: Here we report a microRNA-mediated mechanism by which IFN-γ primes keratinocytes to inflammatory stimuli. Treatment with IFN-γ results in a rapid and long-lasting suppression of miR-149 in keratinocytes. Depletion of miR-149 in keratinocytes leads to widespread transcriptomic changes and induction of inflammatory mediators with enrichment of the TWEAK pathway. We show that IFN-γ-mediated suppression of miR-149 leads to amplified inflammatory responses to TWEAK. TWEAK receptor (TWEAKR/Fn14) is identified as a novel direct target of miR-149. The in vivo relevance of this pathway is supported by decreased miR-149 expression in psoriasis keratinocytes, as well as by the protective effect of synthetic miR-149 in the imiquimod-induced mouse model of psoriasis.CONCLUSION: Our data define a new mechanism, in which IFN-γ primes keratinocytes for TWEAK-induced inflammatory responses through suppression of miR-149, promoting skin inflammation.
  •  
32.
  • Srivastava, Ankit, et al. (författare)
  • Identification of chronological and photoageing-associated microRNAs in human skin.
  • 2018
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • MicroRNAs are short non-coding RNAs that play key roles in regulating biological processes. In this study, we explored effects of chronological and photoageing on the miRNome of human skin. To this end, biopsies were collected from sun-exposed (outer arm, n = 45) and sun-protected (inner arm, n = 45) skin from fair-skinned (phototype II/III) healthy female volunteers of three age groups: young, 18-25 years, middle age, 40-50 years and aged, > 70 years. Strict inclusion criteria were used for photoageing scoring and for chronological ageing. Microarray analysis revealed that chronological ageing had minor effect on the human skin miRNome. In contrast, photoageing had a robust impact on miRNAs, and a set of miRNAs differentially expressed between sun-protected and sun-exposed skin of the young and aged groups was identified. Upregulation of miR-383, miR-145 and miR-34a and downregulation of miR-6879, miR-3648 and miR-663b were confirmed using qRT-PCR in sun-exposed skin compared with sun-protected skin. qRT-PCR analysis revealed that miR-383, miR-34a and miR-134 were differentially expressed in all three age groups both in chronological and photoageing, suggesting a synergetic effect of intrinsic and extrinsic ageing on their expression. In conclusion, our study identifies a unique miRNA signature which may contribute to skin ageing.
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33.
  • Srivastava, Ankit, et al. (författare)
  • MicroRNA-146a suppresses IL-17-mediated skin inflammation and is genetically associated with psoriasis.
  • 2017
  • Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 139:2, s. 550-561
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Psoriasis is an immune-mediated inflammatory skin disease with a strong genetic background in which activation of IL-17 signaling is central in the pathogenesis. Little has been known about the role of noncoding RNAs, including microRNAs (miRNAs), in predisposition to the disease.OBJECTIVE: We sought to investigate the genetic association of single nucleotide polymorphisms in microRNA-146a (miR-146a) to psoriasis and to explore its function in the initiation and resolution of the disease.METHODS: mice in conjunction with the imiquimod-induced mouse model of psoriasis. The severity of psoriasis-like skin inflammation was evaluated at morphologic, histologic, and molecular levels. miR-146a was ectopically overexpressed and inhibited in keratinocytes treated with IL-17. Synthetic miR-146a was injected intradermally into mice.RESULTS: Here we report protective association of a functional polymorphism in the miR-146a precursor (rs2910164). Genetic deficiency in miR-146a leads to earlier onset and exacerbated pathology of skin inflammation, with increased expression of IL-17-induced keratinocyte-derived inflammatory mediators, epidermal hyperproliferation, and increased neutrophil infiltration. Moreover, miR-146a-deficient mice do not resolve inflammation after discontinuation of imiquimod challenge. The overexpression of miR-146a suppressed, whereas its inhibition enhanced, IL-17-driven inflammation in keratinocytes. Functionally, miR-146a impairs the neutrophil chemoattractant capacity of keratinocytes. Finally, delivery of miR-146a mimics into the skin leads to amelioration of psoriasiform skin inflammation, decreased epidermal proliferation, and neutrophil infiltration.CONCLUSIONS: Our results define a crucial role for miR-146a in modulating IL-17-driven inflammation in the skin.
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34.
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35.
  • Srivastava, Ankit, et al. (författare)
  • Tofacitinib Represses the Janus Kinase-Signal Transducer and Activators of Transcription Signalling Pathway in Keratinocytes.
  • 2018
  • Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 98:8, s. 772-775
  • Tidskriftsartikel (refereegranskat)abstract
    • Tofacitinib is a Janus kinase (JAK) inhibitor, which has shown efficacy in treating psoriasis. The mode of action of tofacitinib is not completely understood but it has been thought to be mediated by the inhibition of CD4+ T-cell activation. Here, we investigated whether the molecular targets of tofacitinib are expressed in keratinocytes, and whether tofacitinib can modulate the activity of the JAK/Signal Transducer and Activators of Transcription (STAT)-pathway in keratinocytes. Transcriptomic profiling of human keratinocytes treated with IL-22 in combination with tofacitinib revealed that tofacitinib could prevent the majority of IL-22-mediated gene expression changes. Pathway analysis of tofacitinib-regulated genes in keratinocytes revealed enrichment of genes involved in the JAK/STAT signalling pathway. Quantitative real-time-PCR confirmed the upregulation of S100A7 and downregulation of EGR1 expression by IL-22, which was prevented by tofacitinib pre-treatment. These results indicate a direct effect of tofacinitib on keratinocytes, which can have relevance for systemic as well as for topical treatment of psoriasis with tofacitinib.
  •  
36.
  • Sun, Chengxi, et al. (författare)
  • MicroRNA-23b Plays a Tumor-Suppressive Role in Cutaneous Squamous Cell Carcinoma and Targets Ras-Related Protein RRAS2
  • 2023
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 143:12, s. 2386-2396
  • Tidskriftsartikel (refereegranskat)abstract
    • Cutaneous squamous cell carcinoma (cSCC) is one of the most common types of cancer with metastatic potential. MicroRNAs regulate gene expression at the post-transcriptional level. In this study, we report that miR23b is downregulated in cSCCs and in actinic keratosis and that its expression is regulated by the MAPK signaling pathway. We show that miR-23b suppresses the expression of a gene network associated with key oncogenic pathways and that the miR-23b-gene signature is enriched in human cSCCs. miR-23b decreased the expression of FGF2 both at mRNA and protein levels and impaired the angiogenesis-inducing ability of cSCC cells. miR23b overexpression suppressed the capacity of cSCC cells to form colonies and spheroids, whereas the CRISPR/Cas9-mediated deletion of MIR23B resulted in increased colony and tumor sphere formation in vitro. In accordance with this, miR-23b-overexpressing cSCC cells formed significantly smaller tumors upon injection into immunocompromised mice with decreased cell proliferation and angiogenesis. Mechanistically, we verify RRAS2 as a direct target of miR-23b in cSCC. We show that RRAS2 is overexpressed in cSCC and that interference with its expression impairs angiogenesis and colony and tumorsphere formation. Taken together, our results suggest that miR-23b acts in a tumor-suppressive manner in cSCC, and its expression is decreased during squamous carcinogenesis.
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37.
  • Svedman, Fernanda Costa, et al. (författare)
  • Extracellular microvesicle microRNAs as predictive biomarkers for targeted therapy in metastastic cutaneous malignant melanoma.
  • 2018
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:11
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Mitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers.MATERIALS AND METHODS: EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome.RESULTS: Increased levels of EV let-7g-5p during treatment compared to before treatment (EV let-7g-5p_delta) were associated with better disease control with MAPKis (odds ratio 8568.4, 95% CI = 4.8-1.5e+07, P = 0.000036). Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS) (hazard ratio = 0.27, 95% CI = 0.13-0.52, P <0.000061).CONCLUSIONS: EV miRNAs let-7g-5p and miR-497-5p were identified as putative novel predictive biomarkers of MAPKi treatment benefit in metastatic CMM patients highlighting the potential relevance of assessing EV miRNA during and after treatment to unravel novel mechanisms of resistance.
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38.
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39.
  • Tillett, William, et al. (författare)
  • Nail psoriasis dynamics during biologic treatment and withdrawal in patients with psoriasis who may be at high risk of developing psoriatic arthritis : a post hoc analysis of the VOYAGE 2 randomized trial
  • 2023
  • Ingår i: Arthritis Research & Therapy. - : BioMed Central (BMC). - 1478-6362. ; 25
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Nail psoriasis is a common, physiologically, and psychologically disruptive, and yet often under-treated manifestation of psoriasis. The objectives of this analysis were to investigate the trajectory of nail psoriasis, a risk factor for psoriatic arthritis (PsA), with guselkumab vs adalimumab treatment followed by withdrawal, and determine characteristics associated with nail response in patients treated with guselkumab.Methods: This post hoc analysis of the phase III trial VOYAGE 2 included patients with moderate-to-severe plaque psoriasis and baseline nail involvement. Nail Psoriasis Severity Index (NAPSI) and Psoriasis Area and Severity Index (PASI) were analyzed through week 48 in patients randomized to guselkumab or adalimumab. Multiple logistic regression analyzed factors associated with NAPSI 0/1 at week 24/week 48 following guselkumab treatment. In a separate analysis, patients were stratified by prior biologic experience.Results: Overall, 272 vs 132 patients receiving guselkumab vs adalimumab had nail psoriasis at baseline. Lower baseline NAPSI and week 16 PASI were associated with achieving NAPSI 0/1 at week 24 (NAPSI, odds ratio 0.685 [95% confidence interval: 0.586, 0.802]; week 16 PASI, 0.469 [0.281, 0.782]) and week 48 (NAPSI, 0.784 [0.674, 0.914]; week 16 PASI, 0.557 [0.331, 0.937]) with guselkumab. Previous biologic experience did not impact NAPSI response. Following treatment withdrawal at week 28, mean NAPSI was maintained in the guselkumab arm (week 24 1.7, week 48 1.9) and increased slightly in the adalimumab arm (week 24 1.4, week 48 2.3). Mean PASI increased across both treatment arms.Conclusions: Higher skin efficacy at week 16 was associated with better nail responses during guselkumab treatment. Nail psoriasis improvements reflected skin improvements. Following guselkumab withdrawal, nail response was maintained longer than skin response. Future studies should investigate whether such improvements in nail response reduce patients' risk of later PsA development.
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40.
  • van Huizen, Astrid M., et al. (författare)
  • International eDelphi Study to Reach Consensus on the Methotrexate Dosing Regimen in Patients With Psoriasis
  • 2022
  • Ingår i: JAMA dermatology. - : American Medical Association (AMA). - 2168-6068 .- 2168-6084. ; 158:5, s. 561-561
  • Tidskriftsartikel (refereegranskat)abstract
    • Importance  A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide.Objective  To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics.Design, Setting, and Participants  Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience).Main Outcomes and Measures  In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree.Results  Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In the consensus meeting, consensus was achieved on 4 proposals. More research is needed, especially for the proposals on folic acid and the dosing of methotrexate for treating subpopulations such as children and vulnerable patients.Conclusions and Relevance  In this eDelphi consensus study, consensus was reached on 20 of 21 proposals involving methotrexate dosing in patients with psoriasis. This consensus may potentially be used to harmonize the treatment with methotrexate in patients with psoriasis.
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41.
  • Vegfors, Jenny, 1984- (författare)
  • Psoriasin For Better or for Worse in Sickness and in Health : The Role of Psoriasin in Angiogenesis and Differentation of Epithelial Cells
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Psoriasin (S100A7), a member of the S100 family of calcium-binding proteins, is highly expressed in high-grade ductal carcinoma in situ (DCIS) and in the benign hyper-proliferative skin disorder psoriasis. Both breast cancer and psoriasis are diseases which are characterized by hyperproliferation and a disturbed differentiation of the epithelial cells as well as a pronounced angiogenesis. The potential role of psoriasin in angiogenesis and the epithelial differentiation remain unclear.The aim of this thesis was to investigate the cellular effects of psoriasin in angiogenesis and the differentiation processes, with special emphasis on breast cancer and psoriasis.We found that psoriasin expression was induced in mammary epithelial cells and keratinocytes by oxidative stress. Psoriasin expression was shown to induce vascular endothelial growth factor (VEGF) expression and several other pro-angiogenic factors in epithelial cells. Upon down-regulation of psoriasin, H2O2-induced expression of VEGF was decreased as well as the pro-angiogenic factors heparin-binding EGF-like growth factor (HBEGF) and matrix metalloproteinase (MMP)-1. Extracellular psoriasin contributed to the subsequent induction of proliferation, migration and tube formation of endothelial cells. The proliferative effect of psoriasin was shown to be mediated by the receptor for advanced glycation end products (RAGE). Furthermore, psoriasin induced reactive oxygen species (ROS) in both endothelial and epithelial cells through the action of RAGE, and contributed to the expression of the pro-angiogenic factors in endothelial cells.The expression of psoriasin was up-regulated in mammary epithelial cells and keratinocytes in response to differentiation-inducing stimuli and was shown to be regulated by pathways involved in epithelial cell differentiation. Upon psoriasin down-regulation the shift towards a more differentiated CD24+-phenotype of mammary epithelial cells was abolished. Furthermore, the expression of the differentiation markers involucrin, desmoglein 1, transglutaminase 1 and CD24 was decreased in keratinocytes upon down-regulation of psoriasin expression. In vivo we demonstrated a gradient of psoriasin expression in the psoriatic epidermis, with intense expression in the suprabasal differentiated layers, and a similar staining pattern between psoriasin and the differentiation marker CD24 in DCIS tumors.In conclusion, our findings describe psoriasin as a mediator in the angiogenic process and a contributor of epithelial cell differentiation. Consequently, psoriasin is possibly a contributor to the development and progression of breast cancer and psoriasis and a potential target in the treatment of these diseases.
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42.
  • Villegas, Victoria E, et al. (författare)
  • Identification of novel non-coding RNA-based negative feedback regulating the expression of the oncogenic transcription factor GLI1.
  • 2014
  • Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 8:5, s. 912-26
  • Tidskriftsartikel (refereegranskat)abstract
    • Non-coding RNAs are a complex class of nucleic acids, with growing evidence supporting regulatory roles in gene expression. Here we identify a non-coding RNA located head-to-head with the gene encoding the Glioma-associated oncogene 1 (GLI1), a transcriptional effector of multiple cancer-associated signaling pathways. The expression of this three-exon GLI1 antisense (GLI1AS) RNA in cancer cells was concordant with GLI1 levels. siRNAs knockdown of GLI1AS up-regulated GLI1 and increased cellular proliferation and tumor growth in a xenograft model system. Conversely, GLI1AS overexpression decreased the levels of GLI1, its target genes PTCH1 and PTCH2, and cellular proliferation. Additionally, we demonstrate that GLI1 knockdown reduced GLI1AS, while GLI1 overexpression increased GLI1AS, supporting the role of GLI1AS as a target gene of the GLI1 transcription factor. Activation of TGFβ and Hedgehog signaling, two known regulators of GLI1 expression, conferred a concordant up-regulation of GLI1 and GLI1AS in cancer cells. Finally, analysis of the mechanism underlying the interplay between GLI1 and GLI1AS indicates that the non-coding RNA elicits a local alteration of chromatin structure by increasing the silencing mark H3K27me3 and decreasing the recruitment of RNA polymerase II to this locus. Taken together, the data demonstrate the existence of a novel non-coding RNA-based negative feedback loop controlling GLI1 levels, thus expanding the repertoire of mechanisms regulating the expression of this oncogenic transcription factor.
  •  
43.
  • Wang, Aoxue, et al. (författare)
  • MicroRNA-31 is overexpressed in cutaneous squamous cell carcinoma and regulates cell motility and colony formation ability of tumor cells.
  • 2014
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 134, s. S22-S22
  • Tidskriftsartikel (refereegranskat)abstract
    • Cutaneous squamous cell carcinoma (cSCC) is a malignancy of epidermal keratinocytes that is responsible for approximately 20% of skin cancer-related death yearly. We have previously compared the microRNA (miRNA) expression profile of cSCC to healthy skin and found the dysregulation of miRNAs in human cSCC. In this study we show that miR-31 is overexpressed in cSCC (n = 68) compared to healthy skin (n = 34) and precancerous skin lesions (actinic keratosis, n = 12). LNA in situ hybridization revealed that miR-31 was specifically up-regulated in tumor cells. Mechanistic studies of inhibition of endogenous miR-31 in human metastatic cSCC cells revealed suppressed migration, invasion and colony forming ability, whereas overexpression of miR-31 induced these phenotypes. These results indicate that miR-31 regulates cancer-associated phenotypes of cSCC and identify miR-31 as a potential target for cSCC treatment.
  •  
44.
  • Wei, Tianling, et al. (författare)
  • Interleukin-8 is regulated by miR-203 at the posttranscriptional level in primary human keratinocytes.
  • 2013
  • Ingår i: EJD. European journal of dermatology. - 1167-1122 .- 1952-4013.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: MicroRNAs are important posttranscriptional regulators of gene expression. MiR-203 is a miRNA preferentially expressed in the skin, and an important regulator of keratinocyte differentiation. MiR-203 has been implicated in skin diseases, in particular in psoriasis in which it is overexpressed, and in basal cell carcinoma where it acts as a tumor suppressor miRNA. Objectives: To identify novel targets for miR-203 that may be relevant in skin physiology and diseases. Materials & Methods: Bioinformatics was used to identify putative miR-203 targets among genes expressed in keratinocytes. Interleukin-8 (IL-8) gene expression and concentration in keratinocyte medium was measured by quantitative real-time PCR and ELISA, respectively. For miRNA overexpression, resting or TNF-α-treated primary human keratinocytes were transfected with synthetic precursor of miR-203, or scramble miRNA precursors using Lipofectamine 2000. 3'UTR luciferase reporter experiments were performed to prove the direct miRNA:mRNA interaction. Site-specific mutagenesis was used to mutate the predicted miR-203 binding sites in the 3'UTR of IL-8 gene. Results: Bioinformatic analysis indentified two putative miR-203 binding sites in the 3'UTR of IL-8. MiR-203 suppressed IL-8 mRNA and protein expression in primary human keratinocytes both under resting conditions and after TNF-α treatment. Overexpression of miR-203 suppressed the luciferase activity of a reporter gene fused with the IL-8 3'UTR. The suppressive effect was abolished when the predicted binding sites of miR-203 on IL-8 3'UTR were mutated. Conclusion: We identify IL-8 as a novel target of miR-203 for posttranscriptional suppression. These findings may have relevance in diseases in which miR-203 and IL-8 expression are deregulated.
  •  
45.
  • Wei, Tianling, et al. (författare)
  • The expression of microRNA-203 during human skin morphogenesis.
  • 2010
  • Ingår i: Experimental dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 19:9, s. 854-6
  • Tidskriftsartikel (refereegranskat)abstract
    • MicroRNAs are small, non-coding RNAs that regulate gene expression post-transcriptionally and play important roles in various biological processes. We previously identified miR-203 as a skin- and keratinocyte-specific microRNA. Moreover, miR-203 has been implicated in repressing 'stemness' in epidermal progenitors. Here, we investigate the expression of miR-203 and two of its targets, p63 and suppressor of cytokine signalling-3, during human skin morphogenesis. MiR-203 in situ hybridization was performed on sections of human foetal skin ranging from 14 to 22 weeks' gestation and adult skin. MiR-203 was barely detectable at 14 weeks. Its expression became prominent from week 17 and was most pronounced in the suprabasal layers of the epidermis, while p63 and SOCS-3 were preferentially expressed in the basal layer. Differentiation markers such as involucrin and filaggrin were expressed mainly in the suprabasal layers of epidermis, similar to miR-203. Our results support the involvement of miR-203 in skin morphogenesis.
  •  
46.
  • Xia, Ping, et al. (författare)
  • miR ‐378a regulates keratinocyte responsiveness to interleukin‐17A in psoriasis
  • 2022
  • Ingår i: British Journal of Dermatology. - : John Wiley & Sons. - 0007-0963 .- 1365-2133. ; 187:2, s. 211-222
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Psoriasis is an immune-mediated inflammatory skin disease, in which an interplay between infiltrating immune cells and keratinocytes sustains chronic skin inflammation. Interleukin (IL)-17A is a key inflammatory cytokine in psoriasis and its main cellular targets are keratinocytes.Objectives To explore the role of miR-378a in psoriasis.Methods Keratinocytes obtained from psoriatic skin and healthy epidermis were separated by magnetic sorting, and the expression of miR-378a was analysed by quantitative polymerase chain reaction. The regulation and function of miR-378a was studied using primary human keratinocytes. The expression of miR-378a was modulated by synthetic mimics, and nuclear factor kappa B (NF-κB) activity and transcriptomic changes were studied. Synthetic miR-378a was delivered to mouse skin in conjunction with induction of psoriasiform skin inflammation by imiquimod.Results We show that miR-378a is induced by IL-17A in keratinocytes through NF-κB, C/EBP-β and IκBζ and that it is overexpressed in psoriatic epidermis. In cultured keratinocytes, ectopic expression of miR-378a resulted in the nuclear translocation of p65 and enhanced NF-κB-driven promoter activity even in the absence of inflammatory stimuli. Moreover, miR-378a potentiated the effect of IL-17A on NF-κB nuclear translocation and downstream activation of the NF-κB pathway. Finally, injection of miR-378a into mouse skin augmented psoriasis-like skin inflammation with increased epidermal proliferation and induction of inflammatory mediators. Mechanistically, miR-378a acts as a suppressor of NFKBIA/IκBζ, an important negative regulator of the NF-κB pathway in keratinocytes.Conclusions Collectively, our findings identify miR-378a as an amplifier of IL-17A-induced NF-κB signalling in keratinocytes and suggest that increased miR-378a levels contribute to the amplification of IL-17A-driven skin inflammation in psoriasis.
  •  
47.
  • Xu, Ning, et al. (författare)
  • MicroRNA-125b down-regulates matrix metallopeptidase 13 and inhibits cutaneous squamous cell carcinoma cell proliferation, migration, and invasion.
  • 2012
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 287:35, s. 29899-908
  • Tidskriftsartikel (refereegranskat)abstract
    • Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer. Although dysregulation of microRNAs (miRNAs) is known to be involved in a variety of cancers, the role of miRNAs in cSCC is unclear. In this study, we aimed to identify tumor suppressive and oncogenic miRNAs involved in the pathogenesis of cSCC. MiRNA expression profiles in healthy skins (n = 4) and cSCCs (n = 4) were analyzed using MicroRNA Low Density Array. MiR-125b expression was analyzed by quantitative real-time PCR and in situ hybridization in skin biopsies from 40 healthy donors, 13 actinic keratosis, and 74 cSCC patients. The effect of miR-125b was analyzed in wound closure, colony formation, migration, and invasion assays in two cSCC cell lines, UT-SCC-7 and A431. The genes regulated by miR-125b in cSCC were identified by microarray analysis and its direct target was validated by luciferase reporter assay. Comparing cSCC with healthy skin, we identified four up-regulated miRNAs (miR-31, miR-135b, miR-21, and miR-223) and 54 down-regulated miRNAs, including miR-125b, whose function was further examined. We found that miR-125b suppressed proliferation, colony formation, migratory, and invasive capacity of cSCC cells. Matrix metallopeptidase 13 (MMP13) was identified as a direct target suppressed by miR-125b, and there was an inverse relationship between the expression of miR-125b and MMP13 in cSCC. Knockdown of MMP13 expression phenocopied the effects of miR-125b overexpression. These findings provide a novel molecular mechanism by which MMP13 is up-regulated in cSCCs and indicate that miR-125b plays a tumor suppressive role in cSCC.
  •  
48.
  • Xu, Ning, et al. (författare)
  • MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
  • 2013
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 190:2, s. 678-88
  • Tidskriftsartikel (refereegranskat)abstract
    • Psoriasis is characterized by a specific microRNA expression profile, distinct from that of healthy skin. MiR-31 is one of the most highly overexpressed microRNAs in psoriasis skin; however, its biological role in the disease has not been studied. In this study, we show that miR-31 is markedly overexpressed in psoriasis keratinocytes. Specific inhibition of miR-31 suppressed NF-κB-driven promoter luciferase activity and the basal and TNF-α-induced production of IL-1β, CXCL1/growth-related oncogene-α, CXCL5/epithelial-derived neutrophil-activating peptide 78, and CXCL8/IL-8 in human primary keratinocytes. Moreover, interference with endogenous miR-31 decreased the ability of keratinocytes to activate endothelial cells and attract leukocytes. By microarray expression profiling, we identified genes regulated by miR-31 in keratinocytes. Among these genes, we identified serine/threonine kinase 40 (STK40), a negative regulator of NF-κB signaling, as a direct target for miR-31. Silencing of STK40 rescued the suppressive effect of miR-31 inhibition on cytokine/chemokine expression, indicating that miR-31 regulates cytokine/chemokine expression via targeting STK40 in keratinocytes. Finally, we demonstrated that TGF-β1, a cytokine highly expressed in psoriasis epidermis, upregulated miR-31 expression in keratinocytes in vitro and in vivo. Collectively, our findings suggest that overexpression of miR-31 contributes to skin inflammation in psoriasis lesions by regulating the production of inflammatory mediators and leukocyte chemotaxis to the skin. Our data indicate that inhibition of miR-31 may be a potential therapeutic option in psoriasis.
  •  
49.
  • Xu, Ning, et al. (författare)
  • MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2.
  • 2011
  • Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 131:7, s. 1521-9
  • Tidskriftsartikel (refereegranskat)abstract
    • MicroRNAs (miRNAs) are short, single-stranded, noncoding RNAs that play important roles in the regulation of gene expression. We previously identified a characteristic miRNA expression profile in psoriasis, distinct from that of healthy skin. One of the most downregulated miRNAs in psoriasis skin was microRNA-125b (miR-125b). In this study, we aimed to identify the potential role(s) of miR-125b in psoriasis pathogenesis. In situ hybridization results showed that the major cell type responsible for decreased miR-125b levels in psoriasis lesions was the keratinocyte. Overexpression of miR-125b in primary human keratinocytes suppressed proliferation and induced the expression of several known differentiation markers. Conversely, inhibition of endogenous miR-125b promoted cell proliferation and delayed differentiation. Fibroblast growth factor receptor 2 (FGFR2) was identified as one of the direct targets for suppression by miR-125b by luciferase reporter assay. The expression of miR-125b and FGFR2 was inversely correlated in both transfected keratinocytes and in psoriatic skin. Knocking down FGFR2 expression by siRNA suppressed keratinocyte proliferation, but did not enhance differentiation. Altogether, our results demonstrate a role for miR-125b in the regulation of keratinocyte proliferation and differentiation, partially through the regulation of FGFR2. Loss of miR-125b in psoriasis skin may contribute to hyperproliferation and aberrant differentiation of keratinocytes.
  •  
50.
  • Zitouni, J., et al. (författare)
  • Children with psoriasis and COVID-19 : factors associated with an unfavourable COVID-19 course, and the impact of infection on disease progression (Chi-PsoCov registry)
  • 2022
  • Ingår i: Journal of the European Academy of Dermatology and Venereology. - : John Wiley & Sons. - 0926-9959 .- 1468-3083. ; 36:11, s. 2076-2086
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The COVID-19 pandemic has raised questions regarding the management of chronic skin diseases, especially in patients on systemic treatments. Data concerning the use of biologics in adults with psoriasis are reassuring, but data specific to children are missing. Moreover, COVID-19 could impact the course of psoriasis in children. Objectives The aim of this study was therefore to assess the impact of COVID-19 on the psoriasis of children, and the severity of the infection in relation to systemic treatments. Methods We set up an international registry of paediatric psoriasis patients. Children were included if they were under 18 years of age, had a history of psoriasis, or developed it within 1 month of COVID-19 and had COVID-19 with or without symptoms. Results One hundred and twenty episodes of COVID-19 in 117 children (mean age: 12.4 years) were reported. The main clinical form of psoriasis was plaque type (69.4%). Most children were without systemic treatment (54.2%); 33 (28.3%) were on biologic therapies, and 24 (20%) on non-biologic systemic drugs. COVID-19 was confirmed in 106 children (88.3%) and 3 children had two COVID-19 infections each. COVID-19 was symptomatic for 75 children (62.5%) with a mean duration of 6.5 days, significantly longer for children on non-biologic systemic treatments (P = 0.02) and without systemic treatment (P = 0.006) when compared with children on biologics. The six children who required hospitalization were more frequently under non-biologic systemic treatment when compared with the other children (P = 0.01), and particularly under methotrexate (P = 0.03). After COVID-19, the psoriasis worsened in 17 cases (15.2%). Nine children (8%) developed a psoriasis in the month following COVID-19, mainly a guttate form (P = 0.01). Discussion Biologics appear to be safe with no increased risk of severe form of COVID-19 in children with psoriasis. COVID-19 was responsible for the development of psoriasis or the worsening of a known psoriasis for some children.
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