TGFB3 downregulation causing chordomagenesis and its tumor suppression role maintained by Smad7. (5th April 2021)

• Record Type: Journal Article
• Authors: Wang, Liang; Guan, Xiaonan; Hu, Qingtao; Wu, Zhen; Chen, Wei; Song, Lairong; Wang, Ke; Tian, Kaibing; Cao, Chunwei; Zhang, Dake; Ma, Junpeng; Tong, Xiangjun; Zhang, Bo; Zhang, Junting; Zeng, Changqing
• Is Part Of: Carcinogenesis. Volume 42:Number 7(2021)
• Page Start: 913
• Page End: 923
• Publication Date: 2021-04-05
• Subjects: Carcinogenesis -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Periodicals; 616.994071
• DOI: 10.1093/carcin/bgab022
• Languages: English
• ISSNs: 0143-3334

Abstract

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. Abstract : Downregulation of TGFB3 is associated with the carcinogenesis of chordoma. Exogenesis TGFB3 can inhibit the proliferation, migration and invasion of chordoma cell line through negative feedback of smad7. TGFB signaling pathway may be a feasible target for chordoma therapies.