ZFP36L1 是基因转录本的负调节因子，已被证明可以调节多种癌症的进展。然而，它在肉瘤中的作用仍然未知。在这里，通过数据分析和体内实验，我们发现ZFP36L1抑制骨肉瘤（OS）的肺转移。 ZFP36L1 的敲低通过激活 TGF-β 信号传导和增加 SDC4 表达来促进 OS 细胞迁移。有趣的是，我们观察到 SDC4 和 TGF-β 信号传导之间存在正反馈循环。 SDC4 保护 TGFBR3 免受基质金属蛋白酶 (MMP) 介导的裂解，从而缓解可溶性 TGFBR3 对 TGF-β 信号传导的抑制，而 TGF-β 信号传导正向调节 SDC4 转录。我们还证明，ZFP36L1 通过其 3'UTR 中富含腺苷酸-尿苷酸 (AU) 的元件 (ARE) 调节 SDC4 mRNA 衰减。此外，SB431542（一种 TGF-β 受体激酶抑制剂）和 MK2 抑制剂 III（一种 MAPKAPK2 抑制剂，可增加 ZFP36L1 降解 mRNA 的能力）治疗可显着抑制 OS 肺转移，这表明治疗 OS 肺转移是一种有前途的治疗方法.© 2023。作者。

ZFP36L1, which is a negative regulator of gene transcripts, has been proven to regulate the progression of several carcinomas. However, its role in sarcoma remains unknown. Here, by using data analyses and in vivo experiments, we found that ZFP36L1 inhibited the lung metastasis of osteosarcoma (OS). Knockdown of ZFP36L1 promoted OS cell migration by activating TGF-β signaling and increasing SDC4 expression. Intriguingly, we observed a positive feedback loop between SDC4 and TGF-β signaling. SDC4 protected TGFBR3 from matrix metalloproteinase (MMP)-mediated cleavage and therefore relieved the inhibition of TGF-β signaling by soluble TGFBR3, while TGF-β signaling positively regulated SDC4 transcription. We also proved that ZFP36L1 regulated SDC4 mRNA decay through adenylate-uridylate (AU)-rich elements (AREs) in its 3'UTR. Furthermore, treatment with SB431542 (a TGF-β receptor kinase inhibitor) and MK2 inhibitor III (a MAPKAPK2 inhibitor that increases the ability of ZFP36L1 to degrade mRNA) dramatically inhibited OS lung metastasis, suggesting a promising therapeutic approach for the treatment of OS lung metastasis.© 2023. The Author(s).