Functional Analysis and Clinical Significance of Chloride Channel 2 Expression in Esophageal Squamous Cell Carcinoma
Functional Analysis and Clinical Significance of Chloride Channel 2 Expression in Esophageal Squamous Cell Carcinoma
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DOI：
10.1245/s10434-021-09659-8
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发表时间：
2021-02-09
影响因子：
3.7
通讯作者：
Otsuji, Eigo
中科院分区：
文献类型：
--
作者：
Mitsuda, Masato;Shiozaki, Atsushi;Otsuji, Eigo
背景 最近发现氯离子通道 2 (CLCN2) 会影响肿瘤行为。本研究探讨了 CLCN2 在肿瘤进展中基因调节中的功能，及其在食管鳞状细胞癌 (ESCC) 中的临床病理意义。方法利用CLCN2-小干扰RNA进行敲低实验，研究人ESCC细胞系增殖、存活和细胞运动的变化。对 CLCN2 耗尽的 ESCC 细胞中的基因表达谱进行微阵列分析。通过免疫组织化学 (IHC) 检查 54 个原发性 ESCC 样本。结果 TE5和KYSE70细胞中CLCN2强表达。 CLCN2表达下调可增强增殖并减少细胞凋亡，而其上调则抑制增殖并增加细胞凋亡。还研究了 CLCN2 激活剂鲁比前列酮的作用。在鲁比前列酮处理的细胞中，增殖受到抑制，细胞凋亡增加。微阵列分析表明，干扰素 (IFN) 信号相关基因在 CLCN2 耗尽的细胞中下调。 IHC显示ESCC细胞的细胞质和细胞膜中存在CLCN2。预后分析揭示了 CLCN2 表达较弱与总生存期较短之间的关系。结论 目前的结果表明，CLCN2 通过影响 IFN 信号传导来调节肿瘤进展。此外，CLCN2 表达较弱与 ESCC 患者预后较差相关。本研究将有助于更清楚地了解 CLCN2 作为 ESCC 介质的作用，以及它作为这种癌症生物标志物的用途。
Background Chloride channel 2 (CLCN2) was recently shown to affect tumor behavior. The present study examined the functions of CLCN2 in the regulation of genes that play a role in tumor progression, as well as its clinicopathological significance in esophageal squamous cell carcinoma (ESCC). Methods Knockdown experiments were conducted using CLCN2-small-interfering RNA, and changes in proliferation, survival, and cellular movement in human ESCC cell lines were investigated. A microarray analysis of gene expression profiles in CLCN2-depleted ESCC cells was conducted. Fifty-four primary ESCC samples were examined by immunohistochemistry (IHC). Results The strong expression of CLCN2 was detected in TE5 and KYSE70 cells. Downregulated expression of CLCN2 enhanced proliferation and decreased apoptosis, whereas its upregulation inhibited proliferation and increased apoptosis. The effects of lubiprostone, a CLCN2 activator, were also investigated. In lubiprostone-treated cells, proliferation was inhibited and apoptosis was increased. The microarray analysis demonstrated that interferon (IFN) signaling-related genes were downregulated in CLCN2-depleted cells. IHC showed the presence of CLCN2 in the cytoplasm and cell membranes of ESCC cells. The prognostic analysis revealed a relationship between weak CLCN2 expression and shorter overall survival. Conclusions The present results indicate that tumor progression is regulated by CLCN2 through its effects on IFN signaling. Furthermore, weak CLCN2 expression was associated with poorer outcomes in ESCC patients. The present study will contribute to a clearer understanding of the role of CLCN2 as a mediator of ESCC, as well as its use as a biomarker for this cancer.