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TAZ promotes epithelial to mesenchymal transition via the upregulation of connective tissue growth factor expression in neuroblastoma cells.

Wang Q, Xu Z, An Q, Jiang D, Wang L, Liang B, Li Z - Mol Med Rep (2014)

Bottom Line: The Hippo signaling pathway regulates cell proliferation and apoptosis, and its primary downstream effectors are TAZ and yes‑associated protein 1 (YAP).Repressed expression of TAZ in SK‑N‑BE(2) cells was shown to result in a reduction in aggressiveness of the cell line, by Transwell migration and invasion assay.Furthermore, TAZ was shown by luciferase assay to induce CTGF expression by modulating the activation of the TGF‑β/Smad3 signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.

ABSTRACT
Neuroblastoma (NB) is a neuroendocrine cancer that occurs most commonly in infants and young children. The Hippo signaling pathway regulates cell proliferation and apoptosis, and its primary downstream effectors are TAZ and yes‑associated protein 1 (YAP). The effect of TAZ on the metastatic progression of neuroblastoma and the underlying mechanisms involved remain elusive. In the current study, it was determined by western blot analysis that the migratory and invasive properties of SK‑N‑BE(2) human neuroblastoma cells are associated with high expression levels of TAZ. Repressed expression of TAZ in SK‑N‑BE(2) cells was shown to result in a reduction in aggressiveness of the cell line, by Transwell migration and invasion assay. In contrast, overexpression of TAZ in SK‑N‑SH human neuroblastoma cells was shown by Transwell migration and invasion assays, and western blot analysis, to result in epithelial‑mesenchymal transition (EMT) and increased invasiveness. Mechanistically, the overexpression of TAZ was demonstrated to upregulate the expression levels of connective tissue growth factor (CTGF), by western blot analysis and chromatin immunoprecipitation assay, while the knockdown of TAZ downregulated it. Furthermore, TAZ was shown by luciferase assay to induce CTGF expression by modulating the activation of the TGF‑β/Smad3 signaling pathway. In conclusion, the present study is, to the best of our knowledge, the first to demonstrate that the overexpression of TAZ induces EMT, increasing the invasive abilities of neuroblastoma cells. This suggests that TAZ may serve as a potential target in the development of novel therapies for the treatment of neuroblastoma.

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TAZ induces connective tissue growth factor (CTGF) expression via modulating the activation of the transforming growth factor (TGF)-β/Smad3 signaling pathway. (A) Luciferase reporter assay of CTGF promoter constructs in SK-N-SH cells transiently transfected with indicated plasmids and stimulated with 5 ng/ml TGF-β1 (B) Luciferase reporter assay of CTGF promoter constructs in SK-N-SH cells transiently transfected with indicated plasmids and treated with SB-431542 following stimulation with 5 ng/ml TGF-β1.
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f5-mmr-11-02-0982: TAZ induces connective tissue growth factor (CTGF) expression via modulating the activation of the transforming growth factor (TGF)-β/Smad3 signaling pathway. (A) Luciferase reporter assay of CTGF promoter constructs in SK-N-SH cells transiently transfected with indicated plasmids and stimulated with 5 ng/ml TGF-β1 (B) Luciferase reporter assay of CTGF promoter constructs in SK-N-SH cells transiently transfected with indicated plasmids and treated with SB-431542 following stimulation with 5 ng/ml TGF-β1.

Mentions: Smad3 and Smad4 are the two predominant Smads that form complexes in response to TGF-β and are primarily responsible for the EMT phenotype. Cotransfection of Smad3 and Smad4 in SK-N-SH cells overexpressing TAZ led to a strong induction of CTGF promoter activity compared with that of the untransfected cells (Fig. 5A). In contrast, treatment with SB-431542, a specific and selective inhibitor of TGF-β signaling, inhibited the CTGF promoter activity induced by TAZ (Fig. 5B).


TAZ promotes epithelial to mesenchymal transition via the upregulation of connective tissue growth factor expression in neuroblastoma cells.

Wang Q, Xu Z, An Q, Jiang D, Wang L, Liang B, Li Z - Mol Med Rep (2014)

TAZ induces connective tissue growth factor (CTGF) expression via modulating the activation of the transforming growth factor (TGF)-β/Smad3 signaling pathway. (A) Luciferase reporter assay of CTGF promoter constructs in SK-N-SH cells transiently transfected with indicated plasmids and stimulated with 5 ng/ml TGF-β1 (B) Luciferase reporter assay of CTGF promoter constructs in SK-N-SH cells transiently transfected with indicated plasmids and treated with SB-431542 following stimulation with 5 ng/ml TGF-β1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4262480&req=5

f5-mmr-11-02-0982: TAZ induces connective tissue growth factor (CTGF) expression via modulating the activation of the transforming growth factor (TGF)-β/Smad3 signaling pathway. (A) Luciferase reporter assay of CTGF promoter constructs in SK-N-SH cells transiently transfected with indicated plasmids and stimulated with 5 ng/ml TGF-β1 (B) Luciferase reporter assay of CTGF promoter constructs in SK-N-SH cells transiently transfected with indicated plasmids and treated with SB-431542 following stimulation with 5 ng/ml TGF-β1.
Mentions: Smad3 and Smad4 are the two predominant Smads that form complexes in response to TGF-β and are primarily responsible for the EMT phenotype. Cotransfection of Smad3 and Smad4 in SK-N-SH cells overexpressing TAZ led to a strong induction of CTGF promoter activity compared with that of the untransfected cells (Fig. 5A). In contrast, treatment with SB-431542, a specific and selective inhibitor of TGF-β signaling, inhibited the CTGF promoter activity induced by TAZ (Fig. 5B).

Bottom Line: The Hippo signaling pathway regulates cell proliferation and apoptosis, and its primary downstream effectors are TAZ and yes‑associated protein 1 (YAP).Repressed expression of TAZ in SK‑N‑BE(2) cells was shown to result in a reduction in aggressiveness of the cell line, by Transwell migration and invasion assay.Furthermore, TAZ was shown by luciferase assay to induce CTGF expression by modulating the activation of the TGF‑β/Smad3 signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.

ABSTRACT
Neuroblastoma (NB) is a neuroendocrine cancer that occurs most commonly in infants and young children. The Hippo signaling pathway regulates cell proliferation and apoptosis, and its primary downstream effectors are TAZ and yes‑associated protein 1 (YAP). The effect of TAZ on the metastatic progression of neuroblastoma and the underlying mechanisms involved remain elusive. In the current study, it was determined by western blot analysis that the migratory and invasive properties of SK‑N‑BE(2) human neuroblastoma cells are associated with high expression levels of TAZ. Repressed expression of TAZ in SK‑N‑BE(2) cells was shown to result in a reduction in aggressiveness of the cell line, by Transwell migration and invasion assay. In contrast, overexpression of TAZ in SK‑N‑SH human neuroblastoma cells was shown by Transwell migration and invasion assays, and western blot analysis, to result in epithelial‑mesenchymal transition (EMT) and increased invasiveness. Mechanistically, the overexpression of TAZ was demonstrated to upregulate the expression levels of connective tissue growth factor (CTGF), by western blot analysis and chromatin immunoprecipitation assay, while the knockdown of TAZ downregulated it. Furthermore, TAZ was shown by luciferase assay to induce CTGF expression by modulating the activation of the TGF‑β/Smad3 signaling pathway. In conclusion, the present study is, to the best of our knowledge, the first to demonstrate that the overexpression of TAZ induces EMT, increasing the invasive abilities of neuroblastoma cells. This suggests that TAZ may serve as a potential target in the development of novel therapies for the treatment of neuroblastoma.

Show MeSH
Related in: MedlinePlus