Role of signal transduction and microRNAs on the immunogenicity of melanoma cells

Meyer, Stefanie; Handke, Diana; Müeller, Anja; Meinhardt, Anne; Jasinski‐Bergner, Simon; Mages, Stephan; Bukur, Juergen; Donia, Marco; Straten, Per thor; Seliger, Barbara

doi:10.1186/1479-5876-13-s1-k15

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“…53 Furthermore, the expression of HLA-I molecules and APM components is directly correlated with an improved overall and progression-free survival of melanoma patients in several TCGA datasets. 39,54,55 A reduced mRNA and/or protein expression of various APM components was identified in a large series of melanoma cell lines and lesions, which could be correlated with an increased tumor grading 17,56 implying a deregulated APM component and HLA-I molecule expression. During the last years, some miRs have been reported to target APM components and HLA-I molecules suggesting an important role for post-transcriptional control in the antigen processing and presentation process.…”

Section: Discussionmentioning

confidence: 98%

“…During the last years, some miRs have been reported to target APM components and HLA-I molecules suggesting an important role for post-transcriptional control in the antigen processing and presentation process. 17 So far, only miR-346 has been identified to directly regulate TAP1 during ER stress, 28 suggesting that miRs might be key players and fine tuners of the post-transcriptional regulation of TAP1. 57,58 Their deregulation in melanoma was found by analysis of genomic characteristics of these tumors, which were significantly enriched in miR genes.…”

Section: Discussionmentioning

confidence: 99%

“…11 The characterization of miRs involved in immune evasion mechanisms might contribute to a better understanding of the development and progression of tumors. 17 These deregulated miRs might also improve patients' prognostic classification and provide new diagnostic and therapeutic tools.…”

Section: Introductionmentioning

confidence: 99%

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Identification of miR-200a-5p targeting the peptide transporter TAP1 and its association with the clinical outcome of melanoma patients

et al. 2020

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Tumor escape is often associated with abnormalities in the surface expression of the human leukocyte antigen class I (HLA-I) antigens thereby limiting CD8 + cytotoxic T cell responses. This impaired HLA-I surface expression can be mediated by deficient expression of components of the antigen processing and presentation machinery (APM) due to epigenetic, transcriptional and/or post-transcriptional processes. Since a discordant mRNA and protein expression pattern of APM components including the peptide transporter associated with antigen processing 1 (TAP1) has been frequently described in tumors of distinct origin, a post-transcriptional control of APM components caused by microRNAs (miR) was suggested. Using an in silico approach, miR-200a-5p has been identified as a candidate miR binding to the 3ʹ untranslated region (UTR) of TAP1. Luciferase reporter assays demonstrated a specific binding of miR-200a-5p to the TAP1 3ʹ-UTR. Furthermore, the miR-200a-5p expression is inversely correlated with the TAP1 protein expression in HEK293T cells and in a panel of melanoma cell lines as well as in primary melanoma lesions. High levels of miR-200a-5p expression were associated with a shorter overall survival of melanoma patients. Overexpression of miR-200a-5p reduced TAP1 levels, which was accompanied by a decreased HLA-I surface expression and an enhanced NK cell sensitivity of melanoma cells. These data show for the first time a miRmediated control of the peptide transporter subunit TAP1 in melanoma thereby leading to a reduced HLA-I surface expression accompanied by an altered immune recognition and reduced patients' survival.

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