TGFB3 downregulation causing chordomagenesis and its tumor suppression role maintained by Smad7
Open Access
- 5 April 2021
- journal article
- research article
- Published by Oxford University Press (OUP) in Carcinogenesis: Integrative Cancer Research
- Vol. 42 (7), 913-923
- https://doi.org/10.1093/carcin/bgab022
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.Keywords
Funding Information
- National Natural Science Foundation of China (31701081, 81472370, 81672506, 81101910, 31571271)
- Key Research Program of the Chinese Academy of Sciences (KJZD-EW-L06-2)
- National High Technology Research and Development Program (2012AA022502)
- National Key Basic Research Program (2014CB542006)
- Natural Science Foundation of Beijing Municipality (7142052)
- Ministry of Science and Technology of the People's Republic of China (2012CB945101)
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