Inflammatory and autophagy-related gene P62 is highly expressed in most human tumor tissues. Herein, we demonstrate that P62 promotes human mesenchymal stem cells’ malignant transformation via the cascade of P62-tumor necrosis factor alpha (TNF-α)-CUDR-CTCF-insulin growth factor II (IGFII)-H-Ras signaling. Mechanistically, we reveal P62 enhances IGFII transcriptional activity through forming IGFII promoter-enhancer chromatin loop and increasing METTL3 occupancy on IGFII 3′ UTR and enhances H-Ras overexpression by harboring inflammation-related factors, e.g., TNFR1, CLYD, EGR1, NFκB, TLR4, and PPARγ. Furthermore, the P62 cooperates with TNF-α to promote malignant transformation of mesenchymal stem cells. These findings, for the first time, provide insight into the positive role that P62 plays in malignant transformation of mesenchymal stem cells and reveal a novel link between P62 and the inflammation factors in mesenchymal stem cells.

炎症和自噬相关基因 P62 在大多数人类肿瘤组织中高表达。在此，我们证明 P62 通过 P62-肿瘤坏死因子 α (TNF-α)-CUDR-CTCF-胰岛素生长因子 II (IGFII)-H-Ras 信号通路的级联促进人间充质干细胞的恶性转化。从机制上讲，我们揭示 P62 通过形成 IGFII 启动子-增强子染色质环和增加 METTL3 在 IGFII 3' UTR 上的占据来增强 IGFII 转录活性，并通过携带炎症相关因子（例如 TNFR1、CLYD、EGR1、NFκB、TLR4）增强 H-Ras 过表达和 PPARγ。此外，P62与TNF-α协同促进间充质干细胞的恶性转化。这些发现，第一次，