Department of RNA Biology and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan.
Mol Cancer Res. 2018 May;16(5):880-893. doi: 10.1158/1541-7786.MCR-17-0715. Epub 2018 Jan 12.
Although enhanced thymosin β4 (TMSB4X/Tβ4) expression is associated with tumor progression and metastasis, its tumor-promoting functions remain largely unknown. Here, it is demonstrated that TGFβ facilitates Tβ4 expression and leads to the activation of myocardin-related transcription factors (MRTF), which are coactivators of serum response factor (SRF) and regulate the expression of genes critical for the epithelial-mesenchymal transition (EMT) and tumor metastasis. In murine mammary gland cells (NMuMG), Tβ4 upregulation is required for full induction of a MRTF-regulated EMT gene expression program after TGFβ stimulation. Tβ4 levels are transcriptionally regulated via the novel -acting element AGACAAAG, which interacts with Smad and T-cell factor/lymphoid enhancer factor (TCF/LEF) to synergistically activate the Tβ4 promoter downstream of TGFβ. Murine skin melanoma cells (B16F0 and B16F1) also show the expression regulation of Tβ4 by Smad and TCF/LEF. Tβ4-knockout B16F1 (Tβ4 KO) clones show significantly diminished expression level of tumor-associated genes, which is regulated by the TGFβ/MRTFs pathway. In multiple human cancers, Tβ4 levels correlate positively with TGFβ1 and the tumor-associated gene expression levels through processes that respectively depend on TGFβ receptor 1 (TGFBR1) and MRTF expression. Kaplan-Meier survival analyses demonstrate that high Tβ4 expression associates with poor prognosis in an SRF expression-dependent manner in several cancers. In mice, Tβ4 KO clones show significantly decreased experimental metastatic potential; furthermore, ectopic expression of constitutively active MRTF-A fully restores the diminished metastatic activity. In conclusion, the TGFβ/Tβ4/MRTF/SRF pathway is critical for metastasis and tumor progression. These findings define a molecular mechanism underlying a tumor-promoting function of thymosin β4 through activation of MRTF/SRF signaling. .
尽管增强型胸腺素 β4（TMSB4X/Tβ4）的表达与肿瘤的进展和转移有关，但它的促肿瘤功能在很大程度上仍不清楚。在这里，研究表明 TGFβ 促进 Tβ4 的表达，并导致肌球蛋白相关转录因子（MRTF）的激活，MRTF 是血清反应因子（SRF）的共激活因子，调节上皮-间充质转化（EMT）和肿瘤转移的关键基因的表达。在鼠乳腺细胞（NMuMG）中，Tβ4 的上调是 TGFβ 刺激后完全诱导 MRTF 调节的 EMT 基因表达程序所必需的。Tβ4 的水平通过新的作用元件 AGACAAAG 进行转录调控，该元件与 Smad 和 T 细胞因子/淋巴增强因子（TCF/LEF）相互作用，协同激活 TGFβ 下游的 Tβ4 启动子。鼠皮肤黑色素瘤细胞（B16F0 和 B16F1）也表现出 Smad 和 TCF/LEF 对 Tβ4 的表达调控。Tβ4 敲除 B16F1（Tβ4 KO）克隆显示肿瘤相关基因的表达水平显著降低，这受 TGFβ/MRTFs 途径调控。在多种人类癌症中，Tβ4 水平通过分别依赖于 TGFβ 受体 1（TGFBR1）和 MRTF 表达的过程，与 TGFβ1 和肿瘤相关基因的表达水平呈正相关。Kaplan-Meier 生存分析表明，在几种癌症中，Tβ4 高表达与 SRF 表达依赖性不良预后相关。在小鼠中，Tβ4 KO 克隆显示实验转移潜能显著降低；此外，组成型激活的 MRTF-A 的异位表达完全恢复了转移活性的降低。总之，TGFβ/Tβ4/MRTF/SRF 途径对于转移和肿瘤进展至关重要。这些发现定义了 Tβ4 通过激活 MRTF/SRF 信号促进肿瘤的分子机制。
