Chordoma is a rare bone tumor arising from notochordal remnants, but the underlying mechanism remains elusive. By integrated mRNA and microRNA analyses, we found significant downregulation of TGFB3 along with upregulation of its inhibitor, miR-29 family in chordoma comparing with notochord. Somatic copy number gains of miR-29 loci in chordoma highlighted a mechanism of inactivation of TGFB3 signaling in tumor formation. In zebrafish, knockout and knockdown homologous tgfb3 resulted in a chordoma-like neoplasm. On the other hand, Smad7 negative feedback regulation of transforming growth factor-β (TGF-β) signaling is retentive in chordoma cell UM-Chor1 despite its disruption in most cancer cells (e.g. A549). Therefore, contrary to other cancers, exogenous TGF-β activated Smad7 by downregulating miR-182 and inhibited cell migration and invasion in UM-Chor1. Meanwhile, TGF-β decreased chordoma characteristic protein Brachyury. Altogether, downregulation of TGFB3 causes chordomagenesis, showing a feasible target for therapies. The retention of Smad7 negative regulation may maintain the suppressor role of TGF-β in chordoma.

中文翻译：

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TGFB3 下调导致脊索瘤发生及其由 Smad7 维持的肿瘤抑制作用。

脊索瘤是一种罕见的由脊索残留物引起的骨肿瘤，但其潜在机制仍然难以捉摸。通过整合 mRNA 和 microRNA 分析，我们发现与脊索相比，脊索瘤中 TGFB3 的显着下调及其抑制剂 miR-29 家族的上调。脊索瘤中 miR-29 基因座的体细胞拷贝数增加突出了肿瘤形成中 TGFB3 信号传导失活的机制。在斑马鱼中，敲除和敲除同源 tgfb3 导致脊索瘤样肿瘤。另一方面，Smad7 对转化生长因子-β (TGF-β) 信号传导的负反馈调节在脊索瘤细胞 UM-Chor1 中保留，尽管它在大多数癌细胞（例如 A549）中被破坏。因此，与其他癌症相反，外源性 TGF-β 通过下调 miR-182 激活 Smad7 并抑制 UM-Chor1 中的细胞迁移和侵袭。同时，TGF-β 降低脊索瘤特征蛋白 Brachyury。总而言之，TGFB3 的下调导致脊索瘤发生，显示出治疗的可行目标。Smad7 负调控的保留可能维持 TGF-β 在脊索瘤中的抑制作用。