Fig. 8: Blocking the ZFP36L1-SDC4-TGF-β loop inhibited osteosarcoma EMT and lung metastasis.

In bone lesions, the high expression of ZFP36L1 expedited SDC4 mRNA degradation and reduced SDC4 interacted with TGFBR3, leading to increased free TGFBR3 cleavage by MMP. The increased soluble TGFBR3 (sTGFBR3) subsequently inhibited activation of TGF-β signaling pathway via blocking TGF-β1 binding to TGFBR1/2. Conversely, in metastatic OS cells and lung metastases, the low expression of ZFP36L1 reduced SDC4 mRNA degradation, leading to an abnormal accumulation of SDC4. The interaction between SDC4 and TGFBR3 protected against TGFBR3 cleavage by MMP, resulting in a decrease in extracellular sTGFBR3. The decrease in sTGFBR3 facilitated the activation of the TGF-β signaling pathway by enhancing the binding of TGF-β1 to TGFBR1/2, ultimately resulting in osteosarcoma EMT and lung metastasis. Intriguingly, activation of the TGF-β signaling pathway further upregulated SDC4 expression, which caused a vicious circle. Targeting the ZFP36L1-SDC4-TGF-β loop with MK2 inhibitor III or SB431542 effectively inhibited osteosarcoma EMT and lung metastasis.