Figure 9.

The Schematic Illustrates a Model of Malignant Transformation of Human Mesenchymal Stem Cells via P62-TNF-α-CUDR-CTCF-IGFII-H-Ras Axis Mediated by Long Noncoding RNA CUDR

P62 enhances IGFII transcriptional activity through forming IGFII promoter-enhancer chromatin loop recruiting RNA polII and increasing METTL3 occupancy on IGFII mRNA 3′UTR, which promotes the methylation of IGFII mRNA in mesenchymal stem cells. The excessive IGFII induces the H-Ras overexpression by harboring more inflammation-related factors, e.g., P62, TNFR1, CLYD, EGR1, NFκB, TLR4, and PPARγ onto the H-Ras promoter region. Subsequently, the excessive H-Ras was activated to induce abnormal expression of gene, e.g., Raf, MEKK1, ERK, MEKK4, MEK, Jak, EIK, P38, PI3K, mTOM, and AKT, in the mesenchymal stem cells. Thereby, P62 cooperates with TNF-α to promote mesenchymal stem cells’ malignant transformation.