Abstract
Promoter methylation is one of the most studied epigenetic modifications and it is highly relevant to the onset and progression of thyroid carcinoma (THCA). This study investigates the promoter methylation and expression pattern of intercellular adhesion molecule 5 (ICAM5) in THCA. CpG islands with aberrant methylation pattern in THCA, and the expression profiles of the corresponding genes in THCA, were analyzed using bioinformatics. ICAM5 was suggested to have a hypermethylation status, and it was highly expressed in THCA tissues and cells. Its overexpression promoted proliferation, mobility, and tumorigenic activity of THCA cells. As for the downstream signaling, ICAM5 was found to activate the MAPK/ERK and MAPK/JNK signaling pathways. Either inhibition of ERK or JNK blocked the oncogenic effects of ICAM5. DNA methyltransferases 1 (DNMT1) and DNMT3a were found to induce promoter hypermethylation of ICAM5 in THCA cells. Knockdown of DNMT1 or DNMT3a decreased the ICAM5 expression and suppressed malignant properties of THCA cells in vitro and in vivo, which were, however, restored by further artificial ICAM5 overexpression. Collectively, this study reveals that DNMT1 and DNMT3a mediates promoter hypermethylation and transcription activation of ICAM5 in THCA, which promotes malignant progression of THCA through the MAPK signaling pathway.
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ZBL conceived the study and conducted the main experiments; YY and XTZ were responsible for data collection; JFL and YX conducted the part of the experiments, ZFD and ZQH analyzed and interpreted the data; JJY wrote the manuscript and revised the manuscript and important intellectual content. All authors read and approved the final manuscript.
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The use of human samples was approved by the Institutional Review Board of the First Affiliated Hospital of Gannan Medical College (Approval No. LLSC-2020041215; approved date: 2020.04.12). All included patients signed an informed consent form. All experimental procedures were performed following the guidelines of Declaration of Helsinki. All procedures in our animal experiments were approved by the Animal Ethics and Welfare Committee of the First Affiliated Hospital of Gannan Medical College (Approval No. LLSC-2021082304; approved date: 2021.08.23) and were performed in line with the Guide for the Care and Use of Laboratory Animals: Eighth Edition (2011).
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Li, Z., Ying, Y., Zeng, X. et al. DNMT1/DNMT3a-mediated promoter hypermethylation and transcription activation of ICAM5 augments thyroid carcinoma progression. Funct Integr Genomics 24, 12 (2024). https://doi.org/10.1007/s10142-024-01293-3
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DOI: https://doi.org/10.1007/s10142-024-01293-3