PUBLICATION
TGFB3 downregulation causing chordomagenesis and its tumor suppression role maintained by Smad7
- Authors
- Wang, L., Guan, X., Hu, Q., Wu, Z., Chen, W., Song, L., Wang, K., Tian, K., Cao, C., Zhang, D., Ma, J., Tong, X., Zhang, B., Zhang, J., Zeng, C.
- ID
- ZDB-PUB-210601-17
- Date
- 2021
- Source
- Carcinogenesis 42(7): 913-923 (Journal)
- Registered Authors
- Keywords
- Smad7, TGF-β3, chordoma
- MeSH Terms
-
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism*
- Cell Proliferation
- Chordoma/genetics
- Chordoma/metabolism
- Chordoma/pathology*
- Epithelial-Mesenchymal Transition*
- Gene Expression Regulation, Neoplastic*
- Humans
- Prognosis
- Smad7 Protein/genetics
- Smad7 Protein/metabolism*
- Transforming Growth Factor beta3/antagonists & inhibitors*
- Transforming Growth Factor beta3/genetics
- Transforming Growth Factor beta3/metabolism
- Tumor Cells, Cultured
- PubMed
- 34057989 Full text @ Carcinogenesis
Citation
Wang, L., Guan, X., Hu, Q., Wu, Z., Chen, W., Song, L., Wang, K., Tian, K., Cao, C., Zhang, D., Ma, J., Tong, X., Zhang, B., Zhang, J., Zeng, C. (2021) TGFB3 downregulation causing chordomagenesis and its tumor suppression role maintained by Smad7. Carcinogenesis. 42(7):913-923.
Abstract
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping