論文 - 詳細
| RRC ID | 77027 |
|---|---|
| 著者 | Morita T, Hayashi K. |
| タイトル | Tumor Progression Is Mediated by Thymosin-β4 through a TGFβ/MRTF Signaling Axis. |
| ジャーナル | Mol Cancer Res |
| Abstract |
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 cis-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.Implications: These findings define a molecular mechanism underlying a tumor-promoting function of thymosin β4 through activation of MRTF/SRF signaling. Mol Cancer Res; 16(5); 880-93. ©2018 AACR. |
| 巻・号 | 16(5) |
| ページ | 880-893 |
| 公開日 | 2018-5-1 |
| DOI | 10.1158/1541-7786.MCR-17-0715 |
| PII | 1541-7786.MCR-17-0715 |
| PMID | 29330296 |
| MeSH | Animals Disease Progression Humans Melanoma, Experimental / genetics Melanoma, Experimental / metabolism Melanoma, Experimental / pathology Mice Mice, Inbred C57BL Signal Transduction Thymosin / genetics Thymosin / metabolism* Transfection Transforming Growth Factor beta / genetics Transforming Growth Factor beta / metabolism* |
| IF | 4.63 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | B16F1(RCB2649) |