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TGFB3 downregulation causing chordomagenesis and its tumor suppression role maintained by Smad7
Liang Wang1,2, Xiaonan Guan3,4, Qingtao Hu3,4
1Neurosurgery Department, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili, Dongcheng District, Beijing, China.
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 transforming growth factor-β (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.
Insights
Chordoma, a rare bone cancer, is caused by TGFB3 downregulation. This study reveals TGFB3 as a potential therapeutic target and explains how TGF-β signaling is retained in chordoma cells.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chordoma is a rare bone tumor originating from notochordal remnants, with its underlying pathogenic mechanisms largely unknown.
- Understanding chordoma development is crucial for identifying effective therapeutic strategies.
Purpose of the Study:
- To investigate the molecular mechanisms driving chordoma formation.
- To identify potential therapeutic targets for chordoma treatment.
Main Methods:
- Integrated analysis of mRNA and microRNA expression profiles in chordoma and notochord samples.
- Somatic copy number analysis of microRNA loci.
- Functional studies in zebrafish involving gene knockout and knockdown.
- In vitro experiments using chordoma cell lines to assess the effects of transforming growth factor-β (TGF-β) signaling.
Main Results:
- Significant downregulation of TGFB3 and upregulation of its inhibitor, the miR-29 family, were observed in chordoma compared to notochord.
- Somatic copy number gains of miR-29 loci in chordoma suggest a mechanism for TGFB3 signaling inactivation.
- Zebrafish studies demonstrated that knockout/knockdown of tgfb3 leads to chordoma-like neoplasms.
- Chordoma cells (UM-Chor1) retain Smad7 negative feedback regulation of TGF-β signaling, unlike other cancer cells.
- Exogenous TGF-β inhibited cell migration and invasion in UM-Chor1 by downregulating miR-182 and decreasing Brachyury expression.
Conclusions:
- Downregulation of TGFB3 is a key factor in chordomagenesis, presenting a potential therapeutic target.
- The retained Smad7 negative feedback loop may preserve the tumor-suppressive role of TGF-β signaling in chordoma.
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