Zhang Ya-Qiong, Li Jian, Qin Zhe, Li De-Ming, Ye Fang-Zhou, Bei Song-Hua, Zhang Xiao-Hong, Feng Li
Endoscopy Center, Minhang Hospital Affiliated to Fudan University, Shanghai 201100, China.
World J Gastrointest Oncol. 2024 May 15;16(5):1925-1946. doi: 10.4251/wjgo.v16.i5.1925.
The treatment of gastric cancer (GC) has caused an enormous social burden worldwide. Accumulating studies have reported that N6-methyladenosine (m6A) is closely related to tumor progression. METTL5 is a m6A methyltransferase that plays a pivotal role in maintaining the metabolic stability of cells. However, its aberrant regulation in GC has not been fully elucidated.
To excavate the role of METTL5 in the development of GC.
METTL5 expression and clinicopathological characteristics were analyzed The Cancer Genome Atlas dataset and further verified immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction in tissue microarrays and clinical samples. The tumor-promoting effect of METTL5 on HGC-27 and AGS cells was explored by Cell Counting Kit-8 assays, colony formation assays, scratch healing assays, transwell assays and flow cytometry. The tumor-promoting role of METTL5 was evaluated in a xenograft tumor model. The EpiQuik m6A RNA Methylation Quantification Kit was used for m6A quantification. Next, liquid chromatography-mass spectrometry was used to evaluate the association between METTL5 and sphingomyelin metabolism, which was confirmed by Enzyme-linked immunosorbent assay and rescue tests. In addition, we investigated whether METTL5 affects the sensitivity of GC cells to cisplatin colony formation and transwell experiments.
Our research revealed substantial upregulation of METTL5, which suggested a poor prognosis of GC patients. Increased METTL5 expression indicated distant lymph node metastasis, advanced cancer stage and pathological grade. An increased level of METTL5 correlated with a high degree of m6A methylation. METTL5 markedly promotes the proliferation, migration, and invasion of GC cells . METTL5 also promotes the growth of GC in animal models. METTL5 knockdown resulted in significant changes in sphingomyelin metabolism, which implies that METTL5 may impact the development of GC sphingomyelin metabolism. In addition, high METTL5 expression led to cisplatin resistance.
METTL5 was found to be an oncogenic driver of GC and may be a new target for therapy since it facilitates GC carcinogenesis through sphingomyelin metabolism and cisplatin resistance.
胃癌（GC）的治疗在全球范围内造成了巨大的社会负担。越来越多的研究报告称，N6-甲基腺苷（m6A）与肿瘤进展密切相关。METTL5是一种m6A甲基转移酶，在维持细胞代谢稳定性方面起关键作用。然而，其在GC中的异常调控尚未完全阐明。
挖掘METTL5在GC发生发展中的作用。
分析癌症基因组图谱数据集，利用免疫组织化学、蛋白质免疫印迹法及实时定量聚合酶链反应，在组织芯片和临床样本中进一步验证METTL5的表达及其与临床病理特征的关系。通过细胞计数试剂盒-8法、集落形成实验、划痕愈合实验、Transwell实验及流式细胞术，探讨METTL5对人胃癌细胞系HGC-27和AGS细胞的促肿瘤作用。在异种移植瘤模型中评估METTL5的促肿瘤作用。采用EpiQuik m6A RNA甲基化定量试剂盒进行m6A定量。接下来，利用液相色谱-质谱联用技术评估METTL5与鞘磷脂代谢之间的关联，并通过酶联免疫吸附测定和挽救实验进行验证。此外，通过集落形成和Transwell实验研究METTL5是否影响GC细胞对顺铂的敏感性。
我们的研究显示METTL5显著上调，提示GC患者预后不良。METTL5表达增加表明有远处淋巴结转移、癌症分期进展及病理分级升高。METTL5水平升高与高度m6A甲基化相关。METTL5显著促进GC细胞的增殖、迁移和侵袭。METTL5还促进动物模型中GC的生长。METTL5基因敲低导致鞘磷脂代谢发生显著变化，这意味着METTL5可能通过鞘磷脂代谢影响GC的发生发展。此外，高METTL5表达导致顺铂耐药。
发现METTL5是GC的致癌驱动因子，由于其通过鞘磷脂代谢和顺铂耐药促进GC致癌作用，可能成为新的治疗靶点。
