Gao Shanting, Bu Xiaomin, Gao Yongyue, Bao Zengtao, Shi Wenchao, Luan Lipeng, Chen Huiyu, Zhang Baoming, Tian Qingshui, Guan Wenxian, Yang Liuqing
Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China.
Department of Clinical Laboratory, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
Cell Death Dis. 2022 Apr 19;13(4):376. doi: 10.1038/s41419-022-04832-7.
Gastric cancer (GC) ranks fourth in incidence and mortality worldwide, ascertaining the pathogenesis of GC is crucial for its treatment. E2F1, which regulates the transcription of genes encoding proteins involved in DNA repair, DNA replication, mitosis and survival of cancer patients, functions as a key regulator in GC progression. However, the underneath mechanism of these processes is not fully elucidated. Here, TCGA database analysis, microarray immunohistochemical technique and western blot showed that E2F1 was highly upregulated in clinical GC tissues and correlated with tumor malignancy. In vitro and in vivo assays confirmed the oncogenic function of E2F1. MiR-532 was decreased and negatively correlated with E2F1 in GC tissues. MiR-532 directly targeted and inhibited E2F1 expression, leading to the decrease of ASK1 and elevation of TXNIP, and affected proliferation, cell cycle, apoptosis and DNA damage in vitro and tumor growth in vivo. Moreover, E2F1 serves as a transcriptional repressor to suppress miR-532 expression and a double-negative feedback loop was formed between them. This study demonstrates the significant roles of the E2F1-miR-532 double-negative feedback loop in GC progression and may represent a potential target for GC therapy.
胃癌（GC）的发病率和死亡率在全球范围内位列第四，明确其发病机制对于治疗至关重要。E2F1可调控参与DNA修复、DNA复制、有丝分裂及癌症患者生存的蛋白质编码基因的转录，在胃癌进展中起关键调控作用。然而，这些过程的潜在机制尚未完全阐明。在此，通过TCGA数据库分析、微阵列免疫组化技术及蛋白质印迹法表明，E2F1在临床胃癌组织中高度上调，且与肿瘤恶性程度相关。体内外实验证实了E2F1的致癌功能。在胃癌组织中，miR-532表达降低且与E2F1呈负相关。MiR-532直接靶向并抑制E2F1表达，导致ASK1减少及TXNIP升高，并在体外影响细胞增殖、细胞周期、凋亡及DNA损伤，在体内影响肿瘤生长。此外，E2F1作为转录抑制因子抑制miR-532表达，二者之间形成了一个双负反馈环。本研究证明了E2F1-miR-532双负反馈环在胃癌进展中的重要作用，可能为胃癌治疗提供潜在靶点。
