Differential expression of TGF-β1, TGF-β2, and TGF-β3 across WHO grades in meningioma: convergent evidence from mRNA, methylation, miRNA, and protein analysis

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PURPOSE: Meningiomas show biological heterogeneity not captured by WHO grading alone. TGF-β signaling has been implicated in meningioma pathobiology, yet a systematic, grade-stratified, isoform-resolved characterization of TGF-β1, TGF-β2, and TGF-β3 across transcriptional, epigenetic, post-transcriptional, and protein levels had not been performed. METHODS: We prospectively enrolled 154 patients undergoing resection of WHO CNS5 grade 1 meningothelial (n = 124) or grade 2 atypical (n = 30) meningioma across two neurosurgical centers. TGF-β1-3 mRNA and six bioinformatically prioritized targeting microRNAs were quantified by RT-qPCR; promoter methylation was assessed by methylation-specific PCR; protein abundance was measured by ELISA, Western blotting, and immunohistochemistry. RESULTS: TGF-β2 and TGF-β3 mRNA were markedly upregulated in grade 2 (fold-change 5.68 and 5.23, respectively), corroborated by higher ELISA and IHC signal, though not by Western blot. TGF-β1 mRNA expression was markedly reduced in grade 2 (fold-change 0.039) with reduced protein, despite a predominantly unmethylated promoter (76.7% unmethylated). Nearly all grade 1 specimens showed hypermethylated TGF-β1-3 promoters (95-97%), whereas most grade 2 specimens showed an unmethylated promoter (73-77%). All six candidate microRNAs, notably miR-200a-3p/miR-141-3p, were coordinately downregulated in grade 2. CONCLUSION: These findings show a grade-dependent, isoform-specific pattern of TGF-β dysregulation in meningioma: transcriptional, epigenetic, and post-transcriptional signals converge at the TGF-β2/TGF-β3 axis, alongside a paradoxical reduction in TGF-β1 mRNA that methylation status alone does not explain. This profile nominates TGF-β2/TGF-β3 and the miR-200 family as candidate biomarkers in atypical meningioma, while identifying TGF-β1 regulation as a distinct question for functional follow-up.

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