Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China.
Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang Clinic School of Nanjing Medical University, Zhenjiang, People's Republic of China.
Mol Biomed. 2024 Apr 1;5(1):11. doi: 10.1186/s43556-024-00172-4.
Gastric cancer (GC) is a common malignant tumor worldwide, especially in East Asia, with high incidence and mortality rate. Epigenetic modifications have been reported to participate in the progression of gastric cancer, among which mA is the most abundant and important chemical modification in RNAs. Fat mass and obesity-associated protein (FTO) is the first identified RNA demethylase but little is known about its role in gastric cancer. In our study, data from TCGA and clinical samples showed that FTO was highly expressed in gastric cancer tissues. Kaplan-Meier plotter suggested that patients with the high level of FTO had a poor prognosis. In vitro and in vivo experiments confirmed the role of FTO in promoting gastric cancer cell proliferation. Mechanistically, we found that FTO bound to circFAM192A at the specific site and removed the mA modification in circFAM192A, protecting it from degradation. CircFAM192A subsequently interacted with the leucine transporter solute carrier family 7 member 5 (SLC7A5) and enhancing its stability. As a result, an increased amount of SLC7A5 was on the membrane, which facilitated leucine uptake and activated the mTOR signaling pathway. Therefore, our study demonstrated that FTO promoted gastric cancer proliferation through the circFAM192A/SLC7A5 axis in the mA-dependent manner. Our study shed new light on the role of FTO in gastric cancer progression.
胃癌（GC）是一种常见的恶性肿瘤，在全球范围内，尤其是在东亚地区，发病率和死亡率都很高。已经有报道称，表观遗传修饰参与了胃癌的进展，其中 mA 是 RNA 中最丰富和最重要的化学修饰。脂肪质量和肥胖相关蛋白（FTO）是第一个被鉴定的 RNA 去甲基酶，但关于它在胃癌中的作用知之甚少。在我们的研究中，来自 TCGA 和临床样本的数据表明，FTO 在胃癌组织中高表达。Kaplan-Meier 绘图器表明，FTO 水平高的患者预后不良。体外和体内实验证实了 FTO 在促进胃癌细胞增殖中的作用。在机制上，我们发现 FTO 在特定部位与 circFAM192A 结合，并去除 circFAM192A 中的 mA 修饰，从而保护其免受降解。CircFAM192A 随后与亮氨酸转运蛋白溶质载体家族 7 成员 5（SLC7A5）相互作用，增强其稳定性。结果，更多的 SLC7A5 位于细胞膜上，促进亮氨酸摄取并激活 mTOR 信号通路。因此，我们的研究表明，FTO 通过 circFAM192A/SLC7A5 轴以 mA 依赖的方式促进胃癌增殖。我们的研究为 FTO 在胃癌进展中的作用提供了新的视角。
