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KCNQ1OT1 sponges miR‐34a to promote malignant progression of malignant melanoma via upregulation of the STAT3/PD‐L1 axis
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. 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. 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. 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.
KCNQ1OT1 sponges miR‐34a to promote malignant progression of malignant melanoma via upregulation of the STAT3/PD‐L1 axis
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. 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. 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. 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.
KCNQ1OT1 sponges miR‐34a to promote malignant progression of malignant melanoma via upregulation of the STAT3/PD‐L1 axis
Wang, Xin (author) / Ren, Zhiyao (author) / Xu, Yunfeng (author) / Gao, Xiang (author) / Huang, Hainian (author) / Zhu, Fei (author)
Environmental Toxicology ; 38 ; 368-380
2023-02-01
13 pages
Article (Journal)
Electronic Resource
English
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