Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related mortality worldwide. Methionyl-tRNA synthetase 2 (Mars2) has been suggested as a biomarker indicating poor prognosis of cancers. This study focuses on the function of Mars2 in GC and the responsible molecules. Mars2 was highly expressed in GC patients according to a transcriptome analysis and the data from the public database, and its high expression was confirmed in the acquired GC cell lines. Downregulation of Mars2 significantly weakened the proliferation, resistance to death, migration and invasion of GC cells. The H3K4me3 modification level was increased in the promoter region of Mars2, which was attributed to reduced abundance of lysine demethylase 5D (KDM5D) in the Mars2 promoter. MicroRNA (miR)-4661-5p was identified as an upstream regulator of KDM5D. Downregulation of miR-4661-5p led to an increase in the expression of KDM5D while a decline in the expression of Mars2, which reduced the malignant behaviors of GC cells; however, the malignant behaviors of GC cells was restored after further inhibition of KDM5D. To conclude, this study suggested that increased Mars2 expression upon miR-4661-5p-mediated KDM5D downregulation is correlated with malignant degree of GC cells.

中文翻译：

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microRNA-4661-5p介导的KDM5D下调后Mars2表达增加与胃癌细胞恶性程度相关

胃癌 (GC) 是全球第五大最常见的恶性肿瘤和第三大癌症相关死亡原因。甲硫氨酰-tRNA 合成酶 2 (Mars2) 已被建议作为指示癌症预后不良的生物标志物。本研究的重点是 Mars2 在 GC 中的功能和负责的分子。根据转录组分析和公共数据库的数据，Mars2 在 GC 患者中高表达，并且在获得的 GC 细胞系中证实了其高表达。Mars2的下调显着削弱了GC细胞的增殖、抗死亡、迁移和侵袭。Mars2 启动子区域的 H3K4me3 修饰水平增加，这归因于 Mars2 启动子中赖氨酸去甲基化酶 5D (KDM5D) 的丰度降低。MicroRNA (miR)-4661-5p 被鉴定为 KDM5D 的上游调节因子。miR-4661-5p的下调导致KDM5D的表达增加而Mars2的表达下降，从而减少了GC细胞的恶性行为；然而，在进一步抑制KDM5D后，GC细胞的恶性行为得以恢复。总之，这项研究表明，在 miR-4661-5p 介导的 KDM5D 下调后，Mars2 表达增加与 GC 细胞的恶性程度相关。