Wang Jianding, Zhang Wenwen, Zhang Rui, Yang Hanteng, Li Yitong, Wang Junling, Li Chengyun
Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou 730000, China.
Key Laboratory for Reproductive Medicine and Embryo, The Reproductive Medicine Special Hospital of the Lanzhou University First Affiliated Hospital, Lanzhou 730000, China.
Toxics. 2024 Nov 18;12(11):824. doi: 10.3390/toxics12110824.
N-methyl-n'-nitroso-n'-nitroso guanidine (MNNG) can induce esophageal squamous cell carcinoma (ESCC), and microRNAs are associated with the development of ESCC and may serve as potential tumor prognostic markers. Thus, the aim of this study was to evaluate the potential function of miR-101-3p in MNNG-induced ESCC. An investigation of risk factors in patients with ESCC was carried out and the concentration of nine nitrosamines in urine samples was detected by the SPE-GC-MS technique. Then, we performed cancer tissue gene sequencing analysis, and RT-qPCR verified the expression level of miR-101-3p. Subsequently, the relationship between miR-101-3p potential target genes and the ESCC patients' prognosis was predicted. Finally, we investigated the function of miR-101-3p in MNNG-induced ESCC pathogenesis and the regulatory mechanism of the signaling pathway by in vivo and in vitro experiments. The results revealed that high dietary nitrosamine levels are high-risk factors for ESCC. MiR-101-3p is down-regulated in ESCC tissues and cells, and its potential target genes are enriched in cell migration and cancer-related pathways. MiR-101-3p target genes include AXIN1, CK1, and GSK3, which are involved in the regulation of the Wnt signaling pathway. MiR-101-3p overexpression promotes apoptosis and inhibits the proliferation and migration of Eca109 cells. The Wnt pathway is activated after subchronic exposure to MNNG, and the Wnt pathway is inhibited by the overexpression of miR-101-3p in Eca109 cells. Down-regulated miR-101-3p may exert tumor suppressive effects by regulating the Wnt pathway and may be a useful biomarker for predicting ESCC progression.
N-甲基-N'-亚硝基-N-亚硝基胍（MNNG）可诱发食管鳞状细胞癌（ESCC），且微小RNA与ESCC的发生发展相关，可能作为潜在的肿瘤预后标志物。因此，本研究旨在评估miR-101-3p在MNNG诱导的ESCC中的潜在功能。对ESCC患者的危险因素进行调查，并采用固相萃取-气相色谱-质谱联用技术检测尿液样本中9种亚硝胺的浓度。然后，我们进行癌组织基因测序分析，逆转录定量聚合酶链反应（RT-qPCR）验证miR-101-3p的表达水平。随后，预测miR-101-3p潜在靶基因与ESCC患者预后的关系。最后，通过体内和体外实验研究miR-101-3p在MNNG诱导的ESCC发病机制中的作用及信号通路的调控机制。结果显示，高膳食亚硝胺水平是ESCC的高危因素。miR-101-3p在ESCC组织和细胞中表达下调，其潜在靶基因富集于细胞迁移和癌症相关通路。miR-101-3p的靶基因包括AXIN1、CK1和GSK3，它们参与Wnt信号通路的调控。miR-101-3p过表达促进细胞凋亡，抑制Eca109细胞的增殖和迁移。亚慢性暴露于MNNG后Wnt通路被激活，在Eca109细胞中miR-101-3p过表达可抑制Wnt通路。下调的miR-101-3p可能通过调控Wnt通路发挥肿瘤抑制作用，可能是预测ESCC进展的有用生物标志物。
