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ANGPTL1 attenuates cancer migration, invasion, and stemness through regulating FOXO3a-mediated SOX2 expression in colorectal cancer.

ABSTRACT: Angiopoietin-like protein 1 (ANGPTL1) is a member of the ANGPTL family that suppresses angiogenesis, cancer invasion, metastasis, and cancer progression. ANGPTL1 is down-regulated in various cancers including colorectal cancer (CRC); however, the effects and mechanisms of ANGPTL1 on liver metastasis and cancer stemness in CRC are poorly understood. In the present study, we identified that ANGPTL1 was down-regulated in CRC and inversely correlated with metastasis and poor clinical outcomes in CRC patients form the ONCOMINE database and Human Tissue Microarray staining. ANGPTL1 significantly suppressed the migration/invasion abilities, the expression of cancer stem cell (CSC) markers, and sphere formation by enhancing FOXO3a expression, which contributed to the reduction of stem cell transcription factor SOX2 expression in CRC cells. Consistently, overexpression of ANGPTL1 reduced liver metastasis, tumor growth, and tumorigenicity in tumor-bearing mice. ANGPTL1 expression was negatively correlated with CSC markers expression and poor clinical outcomes in CRC patients. Taken together, these findings demonstrate that the molecular mechanisms of ANGPTL1 in colorectal cancer stem cell progression may provide a novel therapeutic strategy for CRC.

SUBMITTER: Chang TY

PROVIDER: S-EPMC9093149 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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ANGPTL1 attenuates cancer migration, invasion, and stemness through regulating FOXO3a-mediated SOX2 expression in colorectal cancer.

Chang Ting-Yu TY Lan Kuo-Cheng KC Chiu Chen-Yuan CY Sheu Meei-Ling ML Liu Shing-Hwa SH

Clinical science (London, England : 1979) 20220501 9

Angiopoietin-like protein 1 (ANGPTL1) is a member of the ANGPTL family that suppresses angiogenesis, cancer invasion, metastasis, and cancer progression. ANGPTL1 is down-regulated in various cancers including colorectal cancer (CRC); however, the effects and mechanisms of ANGPTL1 on liver metastasis and cancer stemness in CRC are poorly understood. In the present study, we identified that ANGPTL1 was down-regulated in CRC and inversely correlated with metastasis and poor clinical outcomes in CRC ...[more]

PMID: 35475476

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Project description:BackgroundTransmembrane 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.MethodsWe 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.ResultsTM4SF1 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.ConclusionOur 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.

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ANGPTL1 attenuates cancer migration, invasion, and stemness through regulating FOXO3a-mediated SOX2 expression in colorectal cancer.

Publications

ANGPTL1 attenuates cancer migration, invasion, and stemness through regulating FOXO3a-mediated SOX2 expression in colorectal cancer.

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