Endocrine research · 2026
ETV4 transcriptionally activates STAT6 to inhibit ferroptosis and promote immune escape in thyroid cancer.
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Zong Wei, Wang Yancang, Xu Bin
Аннотация
BACKGROUND: Thyroid cancer (THCA) is one of the most common endocrine malignancies, with a significant increase in incidence over the past few decades. ETS variant transcription factor 4 (ETV4) is a member of the ETS family of transcription factors, which play crucial roles in tumorigenesis. However, the precise mechanisms by which ETV4 contributes to THCA progression remain largely unexplored.
METHODS: The expression levels of ETV4, programmed death-ligand 1 (PD-L1), signal transducer and activator of transcription 6 (STAT6), and solute carrier family 7 member 11 (SLC7A11) were analyzed using quantitative reverse transcription PCR (qRT-PCR) and western blotting assays. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. Reactive oxygen species (ROS) levels and apoptosis were evaluated by flow cytometry. Colorimetric assays were employed to measure malondialdehyde (MDA) levels, glutathione (GSH) levels, iron (Fe2+) levels, and lactate dehydrogenase (LDH) cytotoxicity. Enzyme-linked immunosorbent assay (ELISA) was used to quantify interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-2 (IL-2) levels. The interaction between ETV4 and STAT6 was confirmed using a dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay.
RESULTS: ETV4 expression was upregulated in THCA tissues and cells. Its knockdown increased ROS, MDA, and Fe2+, decreased GSH and SLC7A11, and reduced PD-L1 expression. Silencing ETV4 enhanced CD8+ T cell cytotoxicity and elevated secretion of IFN-γ, TNF-α, and IL-2, while promoting apoptosis. STAT6 expression was upregulated in THCA tissues and positively correlated with ETV4 expression. Mechanistically, ETV4 transcriptionally activated STAT6 in FTC-133 cells, and STAT6 overexpression inhibited ferroptosis and promoted immune escape by interacting with ETV4.
CONCLUSION: ETV4 transcriptionally activated STAT6 to inhibit ferroptosis and promote immune escape in THCA. Targeting the ETV4-STAT6 axis may offer a novel therapeutic strategy, potentially inhibiting ferroptosis and enhancing immune response in THCA patients.
METHODS: The expression levels of ETV4, programmed death-ligand 1 (PD-L1), signal transducer and activator of transcription 6 (STAT6), and solute carrier family 7 member 11 (SLC7A11) were analyzed using quantitative reverse transcription PCR (qRT-PCR) and western blotting assays. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. Reactive oxygen species (ROS) levels and apoptosis were evaluated by flow cytometry. Colorimetric assays were employed to measure malondialdehyde (MDA) levels, glutathione (GSH) levels, iron (Fe2+) levels, and lactate dehydrogenase (LDH) cytotoxicity. Enzyme-linked immunosorbent assay (ELISA) was used to quantify interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-2 (IL-2) levels. The interaction between ETV4 and STAT6 was confirmed using a dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay.
RESULTS: ETV4 expression was upregulated in THCA tissues and cells. Its knockdown increased ROS, MDA, and Fe2+, decreased GSH and SLC7A11, and reduced PD-L1 expression. Silencing ETV4 enhanced CD8+ T cell cytotoxicity and elevated secretion of IFN-γ, TNF-α, and IL-2, while promoting apoptosis. STAT6 expression was upregulated in THCA tissues and positively correlated with ETV4 expression. Mechanistically, ETV4 transcriptionally activated STAT6 in FTC-133 cells, and STAT6 overexpression inhibited ferroptosis and promoted immune escape by interacting with ETV4.
CONCLUSION: ETV4 transcriptionally activated STAT6 to inhibit ferroptosis and promote immune escape in THCA. Targeting the ETV4-STAT6 axis may offer a novel therapeutic strategy, potentially inhibiting ferroptosis and enhancing immune response in THCA patients.