TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer
Abstract Background Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive. Methods We investigated the expression of...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2020-11-01
|
Series: | Journal of Experimental & Clinical Cancer Research |
Subjects: | |
Online Access: | http://link.springer.com/article/10.1186/s13046-020-01690-z |
id |
doaj-238ddde5a1d14c9b8006cc6b6eaece81 |
---|---|
record_format |
Article |
spelling |
doaj-238ddde5a1d14c9b8006cc6b6eaece812020-11-25T04:07:04ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662020-11-0139111710.1186/s13046-020-01690-zTM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancerQiang Tang0Jinhuang Chen1Ziyang Di2Wenzheng Yuan3Zili Zhou4Zhengyi Liu5Shengbo Han6Yanwei Liu7Guoguang Ying8Xiaogang Shu9Maojun Di10Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjins Clinical Research Center for CancerDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of General Surgery, Taihe Hospital, Hubei University of MedicineDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of General Surgery, Taihe Hospital, Hubei University of MedicineTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjins Clinical Research Center for CancerDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of General Surgery, Taihe Hospital, Hubei University of MedicineAbstract Background Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive. Methods We investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC. Results TM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model. Conclusion Our study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.http://link.springer.com/article/10.1186/s13046-020-01690-zTM4SF1Colorectal cancerSOX2StemnessEMTWnt/β-catenin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Qiang Tang Jinhuang Chen Ziyang Di Wenzheng Yuan Zili Zhou Zhengyi Liu Shengbo Han Yanwei Liu Guoguang Ying Xiaogang Shu Maojun Di |
spellingShingle |
Qiang Tang Jinhuang Chen Ziyang Di Wenzheng Yuan Zili Zhou Zhengyi Liu Shengbo Han Yanwei Liu Guoguang Ying Xiaogang Shu Maojun Di TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer Journal of Experimental & Clinical Cancer Research TM4SF1 Colorectal cancer SOX2 Stemness EMT Wnt/β-catenin |
author_facet |
Qiang Tang Jinhuang Chen Ziyang Di Wenzheng Yuan Zili Zhou Zhengyi Liu Shengbo Han Yanwei Liu Guoguang Ying Xiaogang Shu Maojun Di |
author_sort |
Qiang Tang |
title |
TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer |
title_short |
TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer |
title_full |
TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer |
title_fullStr |
TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer |
title_full_unstemmed |
TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer |
title_sort |
tm4sf1 promotes emt and cancer stemness via the wnt/β-catenin/sox2 pathway in colorectal cancer |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2020-11-01 |
description |
Abstract Background Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive. Methods We investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC. Results TM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model. Conclusion Our study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC. |
topic |
TM4SF1 Colorectal cancer SOX2 Stemness EMT Wnt/β-catenin |
url |
http://link.springer.com/article/10.1186/s13046-020-01690-z |
work_keys_str_mv |
AT qiangtang tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer AT jinhuangchen tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer AT ziyangdi tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer AT wenzhengyuan tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer AT zilizhou tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer AT zhengyiliu tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer AT shengbohan tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer AT yanweiliu tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer AT guoguangying tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer AT xiaogangshu tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer AT maojundi tm4sf1promotesemtandcancerstemnessviathewntbcateninsox2pathwayincolorectalcancer |
_version_ |
1724429615108194304 |