HERG1 通过激活 PI3K/AKT 通路促进食管鳞癌细胞生长和转移。
HERG1 promotes esophageal squamous cell carcinoma growth and metastasis through TXNDC5 by activating the PI3K/AKT pathway.
机构信息
Cancer Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Department of Oncology, Zhejiang Province Zhoushan Hospital, Zhoushan, China.
出版信息
J Exp Clin Cancer Res. 2019 Jul 22;38(1):324. doi: 10.1186/s13046-019-1284-y.
BACKGROUND
The 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.
METHODS
The 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.
RESULTS
HERG1 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.
CONCLUSIONS
HERG1 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.
背景
人 ether a-go-go 相关基因 1（HERG1）参与肿瘤进展；然而，其在食管鳞状细胞癌（ESCC）中的作用尚未得到充分研究。本研究探讨了 HERG1 在 ESCC 进展中的功能，并阐明了其潜在机制。
方法
通过免疫组织化学法检测 ESCC 活检中 HERG1 的预后价值。通过集落形成和噻唑蓝比色法分析细胞生长和增殖。通过划痕愈合和 Boyden 小室侵袭实验分析细胞迁移和侵袭。通过免疫印迹和定量聚合酶链反应（qPCR）评估上皮-间充质转化（EMT）。使用异种移植小鼠模型在体内验证 HERG1 在致瘤和转移中的作用。
结果
与相邻非肿瘤组织相比，HERG1 在 ESCC 组织中的总体表达水平更高。对 349 例 ESCC（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相关。HERG1 表达较高的患者总体生存率显著较差。HERG1 敲低可减少裸鼠肿瘤生长和转移。HERG1 影响两种 ESCC 细胞系（TE-1 和 KYSE-30）的增殖、迁移和侵袭。HERG1 表达的变化影响细胞周期和 EMT 相关蛋白的表达；这些变化可通过改变与 ESCC 患者的临床病理特征相关且与病理活检中 HERG1 相关的硫氧还蛋白结构域蛋白 5（TXNDC5）的表达来逆转。此外，HERG1 表达改变了磷酸肌醇 3-激酶（PI3K）和 AKT 的磷酸化，从而影响 TXNDC5 的表达。
结论
HERG1 通过 TXNDC5 促进 ESCC 细胞增殖、迁移和侵袭，从而促进 ESCC 患者的不良预后，其通过 PI3K/AKT 信号通路发挥作用。我们的研究结果为 ESCC 的病理学和 HERG1 在肿瘤进展中的作用提供了新的见解，表明针对 HERG1 具有针对 ESCC 治疗的潜在诊断和治疗价值。
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