Abstract
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.
Highlights
Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis
High TM4SF1 expression was significantly associated with poor prognosis We investigated the expression of TM4SF1 in the Oncomine
The Cancer Genome Atlas (TCGA, https://tcgadata.nci. nih.gov/tcga/) and the Gene Expression Omnibus (GEO) databases, and the results suggested that TM4SF1 was significantly upregulated in colorectal cancer (CRC) compared with in adjacent normal tissues (P < 0.01, Fig. 1a, b)
Summary
Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. The role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive. Studies have confirmed that TM4SF1 is highly expressed in various epithelial cancer cells, including pancreatic, liver, lung and bladder cancers [9,10,11]. A previous study reported that TM4SF1 was upregulated in endothelial cells lining angiogenic tumour blood vessels, and they found that TM4SF1 serves as a molecular organizer that is essential for the formation of nanopodia and the maturation of angiogenesis [12]. Most studies about TM4SF1 have mainly focused on TM4SF1 functions as a direct target of some miRNAs (miR-141, miR-9 miR-206) and its biological function in cancer cells [13,14,15]. Further investigation is warranted to identify the downstream target genes of TM4SF1 that are involved in CRC development
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