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      Targeting steroid receptor RNA activator (SRA), a long non-coding RNA, enhances melanogenesis through activation of TRP1 and inhibition of p38 phosphorylation

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          Abstract

          Abnormal skin melanin homeostasis results in refractory pigmentary diseases. Melanogenesis is influenced by gene regulation, ultraviolet radiation, and host epigenetic responses. Steroid receptor RNA activator (SRA), a long noncoding RNA, is known to regulate steroidogenesis and tumorigenesis. However, how SRA contributes to melanogenesis remains unknown. Using RNA interference against SRA in B16 and A375 melanoma cells, we observed increased pigmentation and increased expression of TRP1 and TRP2 at transcriptional and translational levels only in B16 cells. The constitutive phosphorylation of p38 in B16-shCtrl cells was inhibited in cells with knocked down SRAi. Moreover, the melanin content of control B16 cells was increased by SB202190, a p38 inhibitor. Furthermore, reduced p38 phosphorylation, enhanced TRP1 expression, and hypermelanosis were observed in A375 cells with RNA interference. These results indicate that SRA-p38-TRP1 axis has a regulatory role in melanin homeostasis and that SRA might be a potential therapeutic target for treating pigmentary diseases.

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          Most cited references33

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          Noncoding RNAs, cytokines, and inflammation-related diseases.

          Chronic inflammation is involved in the onset and development of many diseases, including obesity, atherosclerosis, type 2 diabetes, osteoarthritis, autoimmune and degenerative diseases, asthma, periodontitis, and cirrhosis. The inflammation process is mediated by chemokines, cytokines, and different inflammatory cells. Although the molecules and mechanisms that regulate this primary defense mechanism are not fully understood, recent findings offer a putative role of noncoding RNAs, especially microRNAs (miRNAs), in the progression and management of the inflammatory response. These noncoding RNAs are crucial for the stability and maintenance of gene expression patterns that characterize some cell types, tissues, and biologic responses. Several miRNAs, such as miR-126, miR-132, miR-146, miR-155, and miR-221, have emerged as important transcriptional regulators of some inflammation-related mediators. Additionally, little is known about the involvement of long noncoding RNAs, long intergenic noncoding RNAs, and circular RNAs in inflammation-mediated processes and the homeostatic imbalance associated with metabolic disorders. These noncoding RNAs are emerging as biomarkers with diagnosis value, in prognosis protocols, or in the personalized treatment of inflammation-related alterations. In this context, this review summarizes findings in the field, highlighting those noncoding RNAs that regulate inflammation, with emphasis on recognized mediators such as TNF-α, IL-1, IL-6, IL-18, intercellular adhesion molecule 1, VCAM-1, and plasminogen activator inhibitor 1. The down-regulation or antagonism of the noncoding RNAs and the administration of exogenous miRNAs could be, in the near future, a promising therapeutic strategy in the treatment of inflammation-related diseases.
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            The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion.

            The identification of cancer-associated long noncoding RNAs (lncRNAs) and the investigation of their molecular and biological functions are important to understand the molecular biology of cancer and its progression. Although the functions of lncRNAs and the mechanisms regulating their expression are largely unknown, recent studies are beginning to unravel their importance in human health and disease. Here, we report that a number of lncRNAs are differentially expressed in melanoma cell lines in comparison to melanocytes and keratinocyte controls. One of these lncRNAs, SPRY4-IT1 (GenBank accession ID AK024556), is derived from an intron of the SPRY4 gene and is predicted to contain several long hairpins in its secondary structure. RNA-FISH analysis showed that SPRY4-IT1 is predominantly localized in the cytoplasm of melanoma cells, and SPRY4-IT1 RNAi knockdown results in defects in cell growth, differentiation, and higher rates of apoptosis in melanoma cell lines. Differential expression of both SPRY4 and SPRY4-IT1 was also detected in vivo, in 30 distinct patient samples, classified as primary in situ, regional metastatic, distant metastatic, and nodal metastatic melanoma. The elevated expression of SPRY4-IT1 in melanoma cells compared to melanocytes, its accumulation in cell cytoplasm, and effects on cell dynamics, including increased rate of wound closure on SPRY4-IT1 overexpression, suggest that the higher expression of SPRY4-IT1 may have an important role in the molecular etiology of human melanoma.
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              Long non-coding RNAs in melanoma

              Melanoma is the most lethal cutaneous cancer with a highly aggressive and metastatic phenotype. While recent genetic and epigenetic studies have shed new insights into the mechanism of melanoma development, the involvement of regulatory non‐coding RNAs remain unclear. Long non‐coding RNAs (lncRNAs) are a group of endogenous non‐protein‐coding RNAs with the capacity to regulate gene expression at multiple levels. Recent evidences have shown that lncRNAs can regulate many cellular processes, such as cell proliferation, differentiation, migration and invasion. In the melanoma, deregulation of a number of lncRNAs, such as HOTAIR, MALAT1, BANCR, ANRIL, SPRY‐IT1 and SAMMSON, have been reported. Our review summarizes the functional role of lncRNAs in melanoma and their potential clinical application for diagnosis, prognostication and treatment.
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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: VisualizationRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: ResourcesRole: SoftwareRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: SoftwareRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                13 August 2020
                2020
                : 15
                : 8
                : e0237577
                Affiliations
                [1 ] Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
                [2 ] Department of Dermatology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
                [3 ] Department of Dermatology, National Yang-Ming University, Taipei, Taiwan
                [4 ] Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
                University of Florida, UNITED STATES
                Author notes

                Competing Interests: All the authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9804-3874
                Article
                PONE-D-19-35767
                10.1371/journal.pone.0237577
                7425936
                32790741
                b1caceb4-b096-497f-b37f-34936874c562
                © 2020 Ho et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 December 2019
                : 29 July 2020
                Page count
                Figures: 4, Tables: 1, Pages: 12
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: MOST105-2314-B-010-054-MY3, 108-2314-B-010-045-MY3
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100011892, Kaohsiung Chang Gung Memorial Hospital;
                Award ID: CORPG8F0021 and CMRPG8D1542
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100011913, Kaohsiung Veterans General Hospital;
                Award ID: VGHKS109-120
                Award Recipient :
                This study was supported by grants from the Taiwan Ministry of Science and Technology (MOST105-2314-B-010-054-MY3, 105-2314-B-182A-001, and 105-2320- B-020-001) and Chang Gung Medical Research Program (CORPG8F0021 and CMRPG8D1542). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Materials Science
                Materials
                Pigments
                Organic Pigments
                Melanin
                Research and Analysis Methods
                Biological Cultures
                Cell Lines
                B16 Cells
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Phosphorylation
                Research and Analysis Methods
                Biological Cultures
                Cell Cultures
                Cultured Tumor Cells
                Melanoma Cells
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                Non-coding RNA
                Long non-coding RNA
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Transfection
                Research and Analysis Methods
                Molecular Biology Techniques
                Transfection
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Epithelial Cells
                Chromatophores
                Melanocytes
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Chromatophores
                Melanocytes
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Chromatophores
                Melanocytes
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Steroids
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Steroids
                Custom metadata
                All relevant data are within the paper.

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