钾离子通道蛋白HERG1通过Cul2上调SCG3促进食管癌进展的机制研究

The potassium channel protein HERG1 has been confirmed to be involved in the regulation of malignant biological behaviors of certain tumors; however, there are few reports on its role in esophageal carcinoma. Our prophase research demonstrated that HERG1 was highly expressed in esophageal carcinoma specimens and could promote esophageal carcinoma cell proliferation and invasion, as well as the epithelial-mesenchymal transition; HERG1 induced upregulation of Cullin2 (Cul2), a member of the ubiquitin ligase family, and secretogranin III (SCG3). However, the linking molecules involved in HERG1, Cul2, and SCG3 are not known. HERG1 has been shown to be involved in regulation of the AKT/NF-κB signaling pathway. Bioinformatics prediction revealed that NF-κB binds to the Cul2 promoter region. Meanwhile, HERG1 modulates the E2F family, which is involved in the regulation of numerous genes. Therefore, we proposed that ①HERG1 enhances the expression of SCG3 by targeting Cul2, thus promoting esophageal carcinoma progression; ②HERG1 regulates Cul2 through the AKT/NF-κB signaling pathway; ③Cul2 regulates SCG3 through the E2F family. This study aimed to explore the role of HERG1 in esophageal carcinoma and clarify the potential relationship between "HERG1-Cul2-SCG3" and esophageal carcinoma progression, thus providing experimental evidence that could be beneficial for the prevention and treatment of esophageal carcinoma.

钾离子通道蛋白HERG1可调控部分肿瘤的恶性生物学行为，但在食管癌中报道有限。我们预实验显示：HERG1在食管癌中高表达，能促进食管癌细胞增殖、侵袭及上皮间质转化；HERG1可上调泛素连接酶家族蛋白Cullin2（Cul2）和分泌粒蛋白III（SCG3），Cul2能促进SCG3表达。但尚不清楚HERG1、Cul2和SCG3中间的桥梁分子。已知HERG1能调控AKT/NF-κB信号轴。同时生物信息学预测：NF-κB能与Cul2启动子区结合。Cul2可调控E2F家族成员，而E2F家族成员能调控多种基因。因此我们假设：①HERG1通过Cul2增强SCG3表达，促进食管癌进展；②HERG1通过AKT/NF-κB信号轴调控Cul2表达；③Cul2通过E2F家族成员上调SCG3。本课题拟探讨HERG1在食管癌中的作用，阐明“HERG1-Cul2-SCG3”与食管癌进展的关系，为食管癌防治提供实验依据。

钾离子通道蛋白HERG1参与肿瘤进展，但HERG1在食管癌中的作用尚未被系统地阐明。本研究旨在探索HERG1在食管癌进展中的作用，并揭示其相关作用机制。我们采用免疫组化法检测食管癌组织标本以明确HERG1的预后价值，采用平板克隆及MTT实验检测细胞生长及增殖能力，采用细胞划痕及transwell侵袭实验检测细胞迁移及侵袭能力。同时，我们应用RT-PCR和western blotting实验检测上皮-间质转化（EMT）相关分子表达情况。裸鼠实验用于证实HERG1在在体水平是否具有促进肿瘤生长和转移的能力。结果提示，HERG1在食管癌组织中的表达量总体上高于癌旁组织。一项针对349例食管癌（I到IV期病例）病人的回顾性分析证实HERG1的高表达意味着食管癌的疾病进展及更高的死亡率。高表达HERG1的食管癌患者总生存率也远远差于低表达HERG1的患者。在裸鼠实验中，沉默HERG1抑制了肿瘤的生长及转移。在食管癌细胞株（TE-1和KYSE-30）中，HERG1能促进肿瘤细胞增殖、迁移和侵袭。同时，HERG1也会影响细胞周期及EMT相关蛋白的表达，而TXNDC5表达的改变可逆转HERG1的上述效应。TXNDC5本身也是与食管癌临床分期和病理分级密切相关的蛋白，且在食管癌标本中TXNDC5与HERG1的表达量呈正相关。不仅如此，HERG1通过促进P13K及AKT的磷酸化而影响TXNDC5的表达。因此，我们推测，HERG1通过P13K/AKT信号通路调控TXNDC5，而这一调控过程能促进食管癌细胞增殖、迁移及侵袭并影响患者预后。我们的研究证实了HERG1在食管癌进展中的作用，并提供了食管癌分子病理学的新观点。因此，HERG1有望成为食管癌诊断及治疗的新靶点。