Tissue & cell · 2026
Knockdown of METTL3 ameliorated myofibroblast activities in oral submucous fibrosis through upregulating DKK3.
СтатьяНазвание и аннотация: Перевод в очереди
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Peng Jing, Guo Sheng, Zhang Peipei
Аннотация
BACKGROUND: Oral submucous fibrosis (OSF) is a precancerous disorder characterized by abnormal buccal mucosal fibroblast (BMF)-to-myofibroblast transition. Dickkopf-related protein 3 (DKK3) is implicated in fibrosis, but its role and regulatory mechanisms in OSF remain unclear.
METHODS: Clinical OSF and normal tissues were analyzed for DKK3 and m6A regulator expression. Arecoline-treated BMFs were used to model OSF in vitro. The mRNA and protein expressions were analyzed by RT-qPCR, Western blot, immunofluorescence staining, and immunohistochemistry. Cell viability, migration, and invasion were detected using CCK-8 assay, wound healing assay, and transwell assay, respectively. Dot blot assay was employed to detect global m6A levels. The interaction between METTL3/YTHDF2 and DKK3 was analyzed by RIP assay. The m6A modification on DKK3 mRNA was analyzed by Me-RIP assay.
RESULTS: DKK3 was downregulated in OSF tissues and arecoline-stimulated BMFs. DKK3 overexpression inhibited arecoline-induced BMF-to-myofibroblast transition. METTL3-mediated m6A modification silenced DKK3 by recruiting YTHDF2, which degraded DKK3 mRNA. As expected, METTL3 knockdown rescued DKK3 expression and inhibited myofibroblast activities, while this effect was reversed by DKK3 co-silencing.
CONCLUSION: The METTL3-m6A-YTHDF2 axis drove OSF progression by promoting BMF-to-myofibroblast transition through suppressing DKK3. Our study provides a research foundation for developing novel therapeutic strategies targeting OSF.
METHODS: Clinical OSF and normal tissues were analyzed for DKK3 and m6A regulator expression. Arecoline-treated BMFs were used to model OSF in vitro. The mRNA and protein expressions were analyzed by RT-qPCR, Western blot, immunofluorescence staining, and immunohistochemistry. Cell viability, migration, and invasion were detected using CCK-8 assay, wound healing assay, and transwell assay, respectively. Dot blot assay was employed to detect global m6A levels. The interaction between METTL3/YTHDF2 and DKK3 was analyzed by RIP assay. The m6A modification on DKK3 mRNA was analyzed by Me-RIP assay.
RESULTS: DKK3 was downregulated in OSF tissues and arecoline-stimulated BMFs. DKK3 overexpression inhibited arecoline-induced BMF-to-myofibroblast transition. METTL3-mediated m6A modification silenced DKK3 by recruiting YTHDF2, which degraded DKK3 mRNA. As expected, METTL3 knockdown rescued DKK3 expression and inhibited myofibroblast activities, while this effect was reversed by DKK3 co-silencing.
CONCLUSION: The METTL3-m6A-YTHDF2 axis drove OSF progression by promoting BMF-to-myofibroblast transition through suppressing DKK3. Our study provides a research foundation for developing novel therapeutic strategies targeting OSF.