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TM4SF1 promotes EMT and cancer stemness via the Wnt/?-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 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-?1 (TGF-?1). 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/?-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/?-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.

SUBMITTER: Tang Q

PROVIDER: S-EPMC7643364 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer.

Tang Qiang Q Chen Jinhuang J Di Ziyang Z Yuan Wenzheng W Zhou Zili Z Liu Zhengyi Z Han Shengbo S Liu Yanwei Y Ying Guoguang G Shu Xiaogang X Di Maojun M

Journal of experimental & clinical cancer research : CR 20201105 1

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 33153498

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Project description:Distant metastasis is, unfortunately, the leading cause of death in colorectal cancer (CRC). Approximately 50% of CRC patients develop liver metastases, while 10-30% of patients develop pulmonary metastases. The occurrence of metastasis is considered to be almost exclusively driven by cancer stem cells (CSCs) formation. However, the key molecules that confer the transformation to stem cells in CRC, and subsequent metastasis, remain unclear. Far upstream element-binding protein 1 (FUBP1), a transcriptional regulator of c-Myc, was screened in CSCs of CRC by mass spectrometry and was examined by immunohistochemistry in a cohort of CRC tissues. FUBP1 was upregulated in 85% of KRAS-mutant and 25% of wild-type CRC patients. Further, whether in KRAS-mutant or wild-type patients, elevated FUBP1 was positively correlated with CRC lymph node metastasis and clinical stage, and negatively associated with overall survival. Overexpression of FUBP1 significantly enhanced CRC cell migration, invasion, tumor sphere formation, and CD133 and ALDH1 expression in vitro, and tumorigenicity in vivo. Mechanistically, FUBP1 promoted the initiation of CSCs by activating Wnt/β-catenin signaling via directly binding to the promoter of DVL1, a potent activator of β-catenin. Knockdown of DVL1 significantly inhibited the transformation to stem cells in, as well as the tumorigenicity of, CRC. Activation of Wnt/β-catenin signaling by DVL1 increased pluripotent transcription factors, including c-Myc, NANOG, and SOX2. Moreover, FUBP1 was upregulated at the post-transcriptional level. Elevated FUBP1 levels in KRAS wild-type CRC patients is due to the decrease in Smurf2, which promotes ubiquitin-mediated degradation of FUBP1. In contrast, FUBP1 was upregulated in KRAS-mutant patients through both inhibition of caspase 3-dependent cleavage and decreased Smurf2. Our results demonstrate, for the first time, that FUBP1 is an oncogene, initiating the development of CSCs, as well as a new powerful endogenous Wnt-signaling agonist that could provide an important prognostic factor and therapeutic target for metastasis in both KRAS-mutant and wild-type CRC.

Dataset Information

TM4SF1 promotes EMT and cancer stemness via the Wnt/?-catenin/SOX2 pathway in colorectal cancer.

Publications

TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer.

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