HERG1 promotes esophageal squamous cell carcinoma growth and metastasis through TXNDC5 by activating the PI3K/AKT pathway
HERG1 promotes esophageal squamous cell carcinoma growth and metastasis through TXNDC5 by activating the PI3K/AKT pathway
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HERG1通过TXNDC5激活PI3K/AKT通路促进食管鳞癌生长和转移
DOI：
10.1186/s13046-019-1284-y
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发表时间：
2019-07-22
影响因子：
11.3
通讯作者：
Xia, Jianling
中科院分区：
文献类型：
--
作者：
Wang, Hongqiang;Yang, Xuchun;Xia, Jianling
背景人类乙醚α-GO-GO相关基因1(HERG1)与肿瘤进展有关，但其在食管鳞癌(ESCC)中的作用尚未得到很好的研究。本研究探讨HERG1在食管癌发生发展中的作用及其机制。方法采用免疫组织化学方法检测HERG1在食管癌组织中的预后价值。用集落形成法和四甲基偶氮唑蓝比色法分析细胞生长和增殖情况。通过创面愈合和Boyden Transwell实验分析细胞的迁移和侵袭。免疫印迹和定量聚合酶链式反应(QPCR)检测上皮-间充质转化(EMT)。用异种移植小鼠模型验证HERG1在体内的致瘤和转移作用。结果食管癌组织中HERG1的表达总体上高于癌旁组织。对349例食管鳞癌(I-IV期)患者的回顾性分析证实，HERG1表达增加与疾病进展和更高的死亡率有关。当他们的肿瘤表现出较高的HERG1表达时，患者的总体生存明显较差。HERG1基因敲除可减少裸鼠的肿瘤生长和转移。HERG1对TE-1和KYSE-30两种食管癌细胞系的增殖、迁移和侵袭均有影响。HERG1表达的改变影响细胞周期和EMT相关蛋白的表达；这些作用可通过改变硫氧还蛋白结构域蛋白5(TXNDC5)的表达而逆转，TXNDC5也与ESCC的临床病理特征有关，并与病理活检中的HERG1相关。此外，HERG1的表达改变了磷脂酰肌醇3-激酶(PI3K)和AKT的磷酸化，从而影响TXNDC5的表达。结论HERG1通过PI3K/AKT信号通路通过TXNDC5促进ESCC细胞的增殖、迁移和侵袭，从而导致预后不良。我们的发现为食管癌的病理机制和HERG1在肿瘤进展中的作用提供了新的见解，提示靶向HERG1对食管癌的治疗具有潜在的诊断和治疗价值。
BackgroundThe human ether a-go-go-related gene 1 (HERG1) is involved in tumor progression; however, its role in esophageal squamous cell carcinoma (ESCC) is not well studied. This study investigated HERG1 function in ESCC progression and elucidated the underlying mechanisms.MethodsThe prognostic value of HERG1 was determined by immunohistochemistry in ESCC biopsies. Cell growth and proliferation were analyzed by colony formation and methyl thiazolyl tetrazolium assays. Cell migration and invasion were analyzed by wound healing and Boyden transwell assays. Epithelial-mesenchymal transition (EMT) was evaluated by immunoblotting and quantitative polymerase chain reaction (qPCR). A xenograft mouse model was used to validate the tumorigenic and metastatic roles of HERG1 in vivo.ResultsHERG1 expression was overall higher in ESCC tissues compared to adjacent non-tumor tissues. A retrospective analysis of 349 patients with ESCC (stages I–IV) confirmed increased HERG1 expression was associated with disease progression and higher mortality rate. The overall survival of the patients was significantly worse when their tumors displayed higher HERG1 expression. HERG1 knockdown reduced tumor growth and metastasis in athymic mice. HERG1 affected the proliferation, migration, and invasion of two ESCC cell lines (TE-1 and KYSE-30). Changes in HERG1 expression affected the expression of cell cycle- and EMT-related proteins; these effects were reversed by altering the expression of thioredoxin domain-containing protein 5 (TXNDC5), which is also associated with the clinicopathological characteristics of patients with ESCC and is relevant to HERG1 in pathological biopsies. Additionally, HERG1 expression altered phosphoinositide 3-kinase (PI3K) and AKT phosphorylation, thereby affecting TXNDC5 expression.ConclusionsHERG1 contributes to poor prognosis in patients with ESCC by promoting ESCC cell proliferation, migration, and invasion via TXNDC5 through the PI3K/AKT signaling pathway. Our findings provided novel insights into the pathology of ESCC and role of HERG1 in tumor progression, suggesting that targeting HERG1 has potential diagnostic and therapeutic value for ESCC treatment.