TCF-1 participates in the occurrence of dedifferentiated chondrosarcoma

Abstract

The present study demonstrated that T cell factor 1 (TCF-1) protein, a component of the canonical Wnt/β-catenin signaling pathway, can regulate the expression of runt-related transcription factor 2 (runx2) gene and Sry-related HMG box 9 (sox9) gene, which may participate in the differentiation of chondrosarcoma. Dedifferentiated chondrosarcoma (DDCS) is a special variant of conventional chondrosarcoma (CCS), associated with poor survival and high metastasis rate. However, little is known about the mechanism of its occurrence; thus, no effective treatment is available except surgery. Earlier, high expression of runx2 and low expression of sox9 were found in DDCS compared with CCS. Using Western blot to detect clinical tissue samples (including 8 CCS samples and 8 DDCS samples) and immunohistochemistry to detect 85 different-grade chondrosarcoma specimens, a high expression of TCF-1 in DDCS tissues was found compared with CCS tissues. This difference in expression was related to patients’ prognosis. Results of luciferase, chromatin immunoprecipitation, and gel electrophoresis mobility shift assays demonstrated that TCF-1 protein could bind to the promoter of runx2 gene directly and sox9 gene indirectly. Hence, it could regulate expression of runx2 gene positively and sox9 gene negatively. Furthermore, in vitro and in vivo experiments showed that TCF-1 protein was closely related to the phenotype and aggressiveness of chondrosarcoma. In conclusion, this study proved that TCF-1 participates in the dedifferentiation of DDCS, which may be mediated by runx2 gene and sox9 gene. Also, TCF-1 can be of important prognostic value and a promising therapeutic target for DDCS patients.

A Shared Regulatory Element Controls the Initiation of Tcf7 Expression During Early T Cell and Innate Lymphoid Cell Developments

“…TCF-1 has been involved in bone formation (38), thermogenesis by brown adipocytes (39), pancreatic β-cell survival and glucose tolerance (40), although the cells in which TCF-1 is expressed are not well defined. Finally, aberrant expression and function of TCF-1 is associated with various diseases, and many cancers (41)(42)(43)(44)(45). Understanding the mechanisms by which TCF1 is regulated in these various cell type could enable us to target TCF-1 expression in specific cell types.…”

HSP90 regulates osteosarcoma cell apoptosis by targeting the p53/TCF‐1‐mediated transcriptional network

“…The LEF/TCF family members are the primary binding complex of the Wnt/β-catenin signaling pathway, which regulates a variety of oncogenic genes, such as c-Myc, Cyclin D1, and Runx2 (Li et al, 2013;Liang et al, 2018;McQueen et al, 2011). Different LEFs/TCFs regulate their target genes in different ways (Hrckulak, Kolar, Strnad, & Korinek, 2016); for instance, TCF-1 and LEF-1 act as transactional Emerging evidence suggests that TCF-1 plays a role in cancers, including chondrosarcoma (Xu et al, 2016). Our results also demonstrated that TCF-1 is overexpressed in OS and is required for its survival.…”

“…In line with this, HSP90 depletion suppressed both the expression of β-catenin and TCF-1 (Figure 3b,c). Because activation of Wnt/β-catenin signaling can be regulated by HSP90 in OS and TCF-1 is essential for β-catenin/TCF-1 complex formation (Liang et al, 2018;Okayama et al, 2014;Xu et al, 2016), we next examined whether the downregulation of TCF-1 involves β-catenin. As shown in Figure 3d, knockdown of β-catenin by siβ-c#3 (siβ-catenin#3) and siβ-c#4 (siβ-catenin#4) further depleted the expression of TCF-1 and Cyclin D1 in Saos-2 cells, indicating that the basal level of β-catenin is required for HSP90-regulated TCF-1 expression.…”

“…TCF-1, also known as transcription factor 7 (TCF7), is well recognized for its role in T-lineage specification and differentiation (Johnson et al, 2018). Accumulating evidence has suggested that TCF-1 is overexpressed in a series of cancers, including prostate cancer, breast cancer, colon cancer, and dedifferentiated chondrosarcoma (Najdi et al, 2009;Park et al, 2015;Xu, Tang, Guo, Yang, & Ren, 2016). The overexpression of TCF-1 in these cancers can be achieved through transcriptional activation of β-catenin signaling, stabilization via inhibition of proteasome degradation, and downregulation of its upstream microRNAs (miRNAs; Lin et al, 2014;Siu et al, 2017;Takahashi-Yanaga et al, 2008;Y.…”

TCF7 knockdown inhibits the imatinib resistance of chronic myeloid leukemia K562/G01 cells by neutralizing the Wnt/β‑catenin/TCF7/ABC transporter signaling axis

“…TCF7 can recognize and bind to the DNA sequence called Wnt response element (WRE) through the HMG domain, cause conformational changes of DNA and chromatin that lead to further binding of other transcription complexes ( 19 ), and promote the expression of Wnt target genes ( 20 ). Previous studies have shown that TCF7 is closely related to the development and progression of various malignancies, such as leukemia ( 21 ), chondrosarcoma ( 22 ), and prostate cancer ( 23 , 24 ). In colorectal tumors, the transcription of Wnt target genes mediated by TCF7 is necessary for the initial activity of tumor stem cells ( 25 ).…”