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Signal Transduction

Tumor Progression Is Mediated by Thymosin-β4 through a TGFβ/MRTF Signaling Axis

Tsuyoshi Morita and Ken'ichiro Hayashi
Tsuyoshi Morita
Department of RNA Biology and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan.
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  • For correspondence: tsuyo@nbiochem.med.osaka-u.ac.jp
Ken'ichiro Hayashi
Department of RNA Biology and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan.
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DOI: 10.1158/1541-7786.MCR-17-0715 Published May 2018
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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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received November 29, 2017.
  • Revision received December 21, 2017.
  • Accepted December 26, 2017.
  • Published first January 12, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Research: 16 (5)
May 2018
Volume 16, Issue 5
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Tumor Progression Is Mediated by Thymosin-β4 through a TGFβ/MRTF Signaling Axis
Tsuyoshi Morita and Ken'ichiro Hayashi
Mol Cancer Res May 1 2018 (16) (5) 880-893; DOI: 10.1158/1541-7786.MCR-17-0715

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Tumor Progression Is Mediated by Thymosin-β4 through a TGFβ/MRTF Signaling Axis
Tsuyoshi Morita and Ken'ichiro Hayashi
Mol Cancer Res May 1 2018 (16) (5) 880-893; DOI: 10.1158/1541-7786.MCR-17-0715
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Molecular Cancer Research
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