TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer.
TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer.
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DOI：
10.1186/s13046-020-01690-z
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发表时间：
2020-11-05
期刊：
影响因子：
--
通讯作者：
Di M
中科院分区：
文献类型：
--
作者：
Tang Q;Chen J;Di Z;Yuan W;Zhou Z;Liu Z;Han S;Liu Y;Ying G;Shu X;Di M
跨膜蛋白4、 、L、6个家族成员1(TM4SF1)在多种上皮性肿瘤中表达上调，与预后不良密切相关。然而，TM4SF1在结直肠癌(CRC)中的作用及其可能的机制仍不清楚。我们研究了TM4SF1在肿瘤、肿瘤基因组图谱(TCGA)和基因表达总集(GEO)数据库中的表达，并通过免疫组织化学(IHC)、定量聚合酶链式反应(QPCR)和Western blotting(WB)对结果进行了验证。通过Transwell法、创面愈合实验和球体形成实验观察TM4SF1对结直肠癌细胞上皮向间充质转化(EMT)和肿瘤干细胞分化的影响。通过一系列的体外和体内实验，揭示了TM4SF1调节结直肠癌EMT和肿瘤干性的机制。TM4SF1在结直肠癌组织中的表达明显高于非肿瘤组织，且与预后不良呈正相关。TM4SF1的下调抑制了SW480和LoVo细胞的迁移、侵袭和肿瘤球体的形成。反之，TM4SF1的过表达显著增强了结直肠癌细胞的迁移、侵袭和肿瘤球体的形成能力，此外，TM4SF1的沉默抑制了转化生长因子-β-1(TGFR-β-1)介导的内皮细胞转化。从机制上讲，基因集浓缩分析(GSEA)预测，与对照相比，Wnt信号通路是TM4SF1缺陷的CRC细胞中受损最严重的通路之一。WB进一步验证了结果，表明TM4SF1以Wnt/β-catenin激活依赖的方式调节SOX2的表达。此外，我们还发现，TM4SF1基因的敲除抑制了c-Myc的表达，导致c-Myc与SOX2基因启动子的结合减少。最后，耗尽TM4SF1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TM4SF1在结直肠癌复发和转移过程中通过Wnt/β-catenin/c-Myc/SOX2轴维持癌细胞干性和转移性的新机制。
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.
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