Yang Yang, Li Wenhua, Wei Bochong, Wu Kai, Liu Donglei, Zhu Dengyan, Zhang Chunyang, Wen Fengbiao, Fan Yuxia, Zhao Song
Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China.
Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, P.R. China.
Mol Ther Nucleic Acids. 2020 Sep 16;22:846-861. doi: 10.1016/j.omtn.2020.09.012. eCollection 2020 Dec 4.
Recent studies have suggested that microRNA let-7i is a tumor suppressor in human cancers, including esophageal cancer, but its underlying mechanism is not yet fully understood. We investigated the role and mechanisms of let-7i in the progression of esophageal cancer. We first showed that let-7i was downregulated in esophageal cancer tissues and cells and then linked its low expression to cancer progression. Bioinformatic analysis predicted KDM5B as a target gene of let-7i, which was confirmed by a dual-luciferase reporter assay. Loss- and gain-of function approaches were adopted to examine the interactions of let-7i, KDM5B, SOX17, and GREB1 and . Overexpression of let-7i suppressed esophageal cancer cell proliferation and invasion and promoted apoptosis. Mechanistic investigation showed that let-7i targeted and inhibited KDM5B expression, whereas KDM5B enhanced H3K4me3 at the SOX17 promoter region. Overexpression of let-7i suppressed the expression of GREB1 in esophageal cancer cells by regulating the KDM5B/SOX17 axis and . Taken together, our findings reveal the tumor-suppressive properties of let-7i in esophageal cancer in association with an apparent KDM5B-dependent SOX17/GREB1 axis. This study offers a potential prognostic marker and therapeutic target for esophageal cancer.
最近的研究表明，微小RNA let-7i在包括食管癌在内的人类癌症中是一种肿瘤抑制因子，但其潜在机制尚未完全阐明。我们研究了let-7i在食管癌进展中的作用和机制。我们首先发现let-7i在食管癌组织和细胞中表达下调，然后将其低表达与癌症进展联系起来。生物信息学分析预测KDM5B是let-7i的靶基因，双荧光素酶报告基因检测证实了这一点。采用功能缺失和功能获得方法来研究let-7i、KDM5B、SOX17和GREB1之间的相互作用。let-7i的过表达抑制了食管癌细胞的增殖和侵袭，并促进了细胞凋亡。机制研究表明，let-7i靶向并抑制KDM5B的表达，而KDM5B增强了SOX17启动子区域的H3K4me3。let-7i的过表达通过调节KDM5B/SOX17轴抑制了食管癌细胞中GREB1的表达。综上所述，我们的研究结果揭示了let-7i在食管癌中的肿瘤抑制特性，以及明显的KDM5B依赖性SOX17/GREB1轴。本研究为食管癌提供了一个潜在的预后标志物和治疗靶点。
