KCNQ1OT1 sponges miR-34a to promote malignant progression of malignant melanoma via upregulation of the STAT3/PD-L1 axis.
Environ Toxicol
; 38(2): 368-380, 2023 Feb.
Article
em En
| MEDLINE
| ID: mdl-36399467
ABSTRACT
BACKGROUND:
Malignant melanoma is a leading cause of skin cancer-related death. In over 30% of cases, the melanoma is invasive and has a metastatic phenotype. KCNQ1 overlapping transcript 1 (KCNQ1OT1) was previously identified as an oncogenic long noncoding RNA (lncRNA). Our study intends to uncover the mechanism of KCNQ1OT1 functioning in melanoma.METHODS:
qRT-PCR, immunohistochemical analysis, and Western blotting were used to investigate mechanisms of the lncRNA KCNQ1OT1, on its downstream genes in melanoma tissues, cells as well as the impact on CD8+ T cells. Proliferation, apoptosis, and migration/invasion were assessed in melanoma cells to evaluate the effects of KCNQ1OT1, miR-34a, and signal transducer and activator of transcription 3 (STAT3). The RNA interactions were determined by dual-luciferase reporter, and melanoma cells were co-cultured with CD8+ T cells to study immune evasion. A lactate dehydrogenase (LDH) cytotoxicity assay was used to investigate the cytotoxicity of CD8+ T cells toward melanoma cells. The in vivo tumorigenic potential of KCNQ1OT1 was defined using xenograft models.RESULTS:
KCNQ1OT1 was upregulated in melanoma tissues leading to a poor prognosis, and knocking down it inhibited melanoma cell proliferation, migration, and invasion. KCNQ1OT1 regulated the progression of the melanoma via its action as a miR-34a sponge. STAT3 was found to be a downstream target of miR-34a, resulting in transcriptional regulation of Programmed cell death 1 ligand 1 (PD-L1). KCNQ1OT1 regulated STAT3 by targeting miR-34a. Knockdown of KCNQ1OT1 reduced PD-L1 level, enhanced CD8+ T cell cytotoxicity, and proliferation and inhibited apoptosis of CD8+ T cells.CONCLUSION:
Melanoma cells overexpressed KCNQ1OT1, which influenced the miR-34a/STAT3 axis, to promote proliferation, migration, and invasion of melanoma cells. In addition, KCNQ1OT1 inhibited CD8+ T cell function, also via the miR-34a/STAT3/PD-L1 axis, thus promoting immune evasion of melanoma cells. The current findings expose a potential therapeutic target of melanoma.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
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MicroRNAs
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RNA Longo não Codificante
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Melanoma
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article