The transcription factor LEF1 promotes tumorigenicity and activates the TGF-β signaling pathway in esophageal squamous cell carcinoma
The transcription factor LEF1 promotes tumorigenicity and activates the TGF-β signaling pathway in esophageal squamous cell carcinoma
复制标题
DOI：
10.1186/s13046-019-1296-7
复制
发表时间：
2019-07-11
影响因子：
11.3
通讯作者：
Chen, Hezhong
中科院分区：
文献类型：
--
作者：
Zhao, Yue;Zhu, Ji;Chen, Hezhong
背景食管鳞状细胞癌（Esophageal squamous cell carcinoma，ESCC）是食管癌中最难治疗的一种亚型，由于缺乏有效的靶向治疗手段，ESCC患者的生存率和复发率均较低。ESCC被认为是由癌症干细胞（CSC）引起的，其有助于转移和化学抗性。尽管在诊断和治疗方面取得了进展，但ESCC患者的预后仍然很差。方法在本研究中，我们应用western blot，定量实时聚合酶链反应（qRT-PCR），免疫组织化学，RNA-Seq分析，荧光素酶报告基因分析，芯片qPCR，生物信息学分析，并通过一系列的功能检测来显示LEF 1在调节食管CSCs中的潜在作用。与异常的临床病理特征和食管鳞癌患者的不良预后相关。此外，LEF 1和OV 6的高表达与异常的临床病理特征和不良的患者预后显著相关。此外，LEF 1的过度表达观察到在食管癌干细胞的粘附和球形ESCC细胞的磁性分选纯化。CSC中LEF 1水平的增加促进了CSC标志物的表达、干细胞样特性、对化疗的抗性和致瘤性，并增加了ESCC样本中CSC的百分比。相反，LEF 1的敲低显著降低了ESCC的自我更新特性。我们发现LEF 1通过直接结合ID 1基因启动子在激活TGF-β信号通路中发挥重要的机械作用。LEF 1和ID 1表达之间的正相关性也观察到在临床ESCC samples.ConclusionOur结果表明，LEF 1的过度表达促进CSC样表型和肿瘤的ESCC通过激活TGF-β信号通路。因此，抑制LEF 1可能是一种新的治疗靶点，以抑制肿瘤的进展。
BackgroundEsophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to the paucity of effective targeted therapy. ESCC is believed to arise from cancer stem cells (CSCs) that contribute to metastasis and chemoresistance. Despite advances in diagnosis and treatment, the prognosis of ESCC patients remains poor.MethodsIn this study, we applied western blot, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry, RNA-Seq analysis, luciferase reporter assay, Chip-qPCR, bioinformatics analysis, and a series of functional assays to show the potential role of LEF1 in regulating esophageal CSCs.ResultsWe found that the overexpression of LEF1 was associated with aberrant clinicopathological characteristics and the poor prognosis of ESCC patients. In addition, the elevated expression of LEF1 and OV6 was significantly associated with aberrant clinicopathological features, and poor patient prognosis. Moreover, the overexpression of LEF1 was observed in esophageal CSCs purified by the magnetic sorting of adherent and spheroidal ESCC cells. The increased level of LEF1 in CSCs facilitated the expression of CSC markers, stem cell-like properties, resistance to chemotherapy, and tumorigenicity and increased the percentage of CSCs in ESCC samples. Conversely, the knockdown of LEF1 significantly diminished the self-renewal properties of ESCC. We showed that LEF1 played an important mechanical role in activating the TGF-beta signaling pathway by directly binding to the ID1 gene promoter. A positive association between LEF1 and ID1 expression was also observed in clinical ESCC samples.ConclusionOur results indicate that the overexpression of LEF1 promotes a CSC-like phenotype in and the tumorigenicity of ESCC by activating the TGF-beta signaling pathway. The inhibition of LEF1 might therefore be a novel therapeutic target to inactivate CSCs and inhibit tumor progression.