Zic family member 2 (ZIC2) is closely associated with cancer development, however, its role in the progression of osteosarcoma (OS) remains unknown. This study aims to reveal the function of ZIC2 in OS cell tumor progression and the underlying mechanism. This work performed quantitative real-time polymerase chain reaction to detect mRNAlevels of ZIC2, retinoic acid receptor alpha (RARA) and methyltransferase 3,N6-adenosine-methyltransferase complex catalytic subunit (METTL3),whereas protein level was detected by western blotting assay and immunohistochemistry assay. CCK-8 together with 5-Ethynyl-2'-deoxyuridine (EdU) assay were performed to analyze cell growth. Cell apoptosis was assessed by flow cytometry. Transwell assay and wound-healing assay were used for measuring cell invasion and migration. A xenograft mouse model assay was conducted to reveal the effect of ZIC2 on tumor formation invivo. The association of ZIC2 and METTL3 was identified by m6A RNA immunoprecipitation assay, dual-luciferase reporter gene assay, Actinomycin D assay and co-immunoprecipitation assay. ZIC2and METTL3 mRNA expression were upregulated in OS tissues relative to paracancerous normal tissues. ZIC2 was a prognostic biomarker for OS,and its expression was significantly associated with TNM stage, lymph node metastasis, and tumor size of OS patients. Additionally, ZIC2depletion inhibited proliferation, invasion and migration and induced apoptosis of OS cells, but ZIC2 overexpression had the opposite effects. Moreover, ZIC2 knockdown delayed tumor formation invivo. METTL3stabilized ZIC2 mRNA through m6A methylation modification. Further,METTL3 deficiency repressed OS cell malignancy by reducing ZIC2expression. METTL3-mediated m6Amodification of ZIC2 contributed to OS development, providing therapeutic targets for OS.
Liu et al. (Wed,) studied this question.
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