Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjins Clinical Research Center for Cancer, Tianjin, 300060, China.
Department of General Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China.
J Exp Clin Cancer Res. 2020 Nov 5;39(1):232. doi: 10.1186/s13046-020-01690-z.
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.
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.
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.
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.
跨膜 4 超家族成员 1（TM4SF1）在几种上皮癌中上调，与预后不良密切相关。然而，TM4SF1 在结直肠癌（CRC）中的作用及其潜在机制仍不清楚。
我们在 Oncomine、癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）中研究了 TM4SF1 的表达，并通过免疫组织化学（IHC）、qPCR 和 Western blot（WB）对 CRC 组织的结果进行了验证。通过 Transwell、划痕愈合和球体形成实验研究了 TM4SF1 对 CRC 细胞上皮-间充质转化（EMT）和癌症干性的影响。进行了一系列体外和体内实验，以揭示 TM4SF1 调节 CRC 中 EMT 和癌症干性的机制。
TM4SF1 在 CRC 组织中的表达明显高于非肿瘤组织，与预后不良呈正相关。TM4SF1 的下调抑制了 SW480 和 LoVo 细胞的迁移、侵袭和肿瘤球体形成。相反，TM4SF1 的过表达显著增强了 CRC 细胞的迁移、侵袭和肿瘤球体形成能力。此外，TM4SF1 沉默抑制了转化生长因子-β1（TGF-β1）介导的 EMT。通过基因集富集分析（GSEA）预测，与对照组相比，TM4SF1 缺陷型 CRC 细胞中 Wnt 信号通路是受影响最严重的途径之一。WB 进一步验证了这一结果，表明 TM4SF1 通过 Wnt/β-catenin 激活依赖性方式调节 SOX2 的表达。此外，我们发现 TM4SF1 的敲低抑制了 c-Myc 的表达，导致 c-Myc 与 SOX2 基因启动子结合减少。最后，TM4SF1 的耗竭抑制了异种移植小鼠模型中的转移和肿瘤生长。
我们的研究证实了一种新的机制，即 TM4SF1 通过 Wnt/β-catenin/c-Myc/SOX2 轴在 CRC 复发和转移过程中维持癌细胞干性和 EMT。
Zotero 插件
