An Tong-Yan, Hu Quan-Man, Ni Peng, Hua Yan-Qiao, Wang Di, Duan Guang-Cai, Chen Shuai-Yin, Jia Bin
Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China.
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
World J Gastrointest Oncol. 2024 Jul 15;16(7):3270-3283. doi: 10.4251/wjgo.v16.i7.3270.
() colonizes the human gastric mucosa and is implicated in the development of gastric cancer (GC). The tumor microenvironment is characterized by hypoxia, where hypoxia-inducible factor-1α (HIF-1α) plays a key role as a transcription factor, but the mechanisms underlying -induced HIF-1α expression and carcinogenesis remain unclear.
To explore the underlying mechanism of -induced HIF-1α expression in promoting the malignant biological behavior of gastric epithelial cells (GES-1).
The study was conducted with human GES-1 cells . Relative protein levels of methyltransferase-like protein 14 (METTL14), HIF-1α, main proteins of the PI3K/AKT pathway, epithelial-mesenchymal transition (EMT) biomarkers, and invasion indicators were detected by Western blot. Relative mRNA levels of and were detected by quantitative reverse transcription-polymerase chain reaction. mRNA stability was evaluated using actinomycin D, and the interaction between METTL14 and HIF-1α was confirmed by immunofluorescence staining. Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay, respectively.
promoted HIF-1α expression and activated the PI3K/AKT pathway. Notably, METTL14 was downregulated in -infected gastric mucosal epithelial cells and positively regulated HIF-1α expression. Functional experiments showed that the overexpression of HIF-1α or knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway, thereby driving a series of malignant transformation, such as EMT and cell proliferation, migration, and invasion. By contrast, the knockdown of HIF-1α or overexpression of METTL14 had an opposite effect.
induced underexpression of METTL14 promotes the translation of HIF-1α and accelerates tumor progression by activating the PI3K/AKT pathway. These results provide novel insights into the carcinogenesis of GC.
（某因素）定殖于人类胃黏膜并与胃癌（GC）的发生有关。肿瘤微环境以缺氧为特征，其中缺氧诱导因子-1α（HIF-1α）作为转录因子发挥关键作用，但（该因素）诱导HIF-1α表达及致癌的机制仍不清楚。
探讨（该因素）诱导HIF-1α表达促进胃上皮细胞（GES-1）恶性生物学行为的潜在机制。
用人GES-1细胞进行该研究。通过蛋白质免疫印迹法检测甲基转移酶样蛋白14（METTL14）、HIF-1α、PI3K/AKT途径主要蛋白、上皮-间质转化（EMT）生物标志物及侵袭指标的相对蛋白水平。通过定量逆转录-聚合酶链反应检测（相关基因）的相对mRNA水平。用放线菌素D评估mRNA稳定性，通过免疫荧光染色确认METTL14与HIF-1α之间的相互作用。分别通过细胞计数试剂盒-8法和伤口愈合试验评估细胞增殖和迁移。
（该因素）促进HIF-1α表达并激活PI3K/AKT途径。值得注意的是，METTL14在（该因素）感染的胃黏膜上皮细胞中下调，并正向调节HIF-1α表达。功能实验表明，HIF-1α的过表达或METTL14的敲低增强了PI3K/AKT途径的活性，从而驱动一系列恶性转化，如EMT以及细胞增殖、迁移和侵袭。相比之下，HIF-1α的敲低或METTL14的过表达则产生相反的效果。
（该因素）诱导的METTL14低表达通过激活PI3K/AKT途径促进HIF-1α的翻译并加速肿瘤进展。这些结果为GC的致癌机制提供了新的见解。
