Jian Jiabei, Feng Yanlu, Wang Ruiying, Li Chengyun, Zhang Lin, Ruan Ye, Luo Bin, Liang Geyu, Liu Tong
Institute of Occupational Health and Environmental Health, School of Public Health, Lanzhou University, Lanzhou 730000, China.
Qinghai Provincial Center for Disease Control and Prevention, Institute of Immunization Planning, Xining 810000, China.
Toxics. 2024 Aug 6;12(8):573. doi: 10.3390/toxics12080573.
As a representative item of chemical carcinogen, MNNG is closely associated with the onset of gastric cancer (GC), where N6-methyladonosine (m6A) RNA methylation is recognized as a critical epigenetic event. In our previous study, we found that the m6A modification by methyltransferase METTL3 was up-regulated in MNNG-exposed malignant GES-1 cells (MC cells) compared to control cells in vitro, and long non-coding RNA SNHG7 as a downstream target of the METTL3. However, the functional role of METTL3 in mediating the SNHG7 axis in MNNG-induced GC remains unclear. In the present study, we continuously investigate the functional role of METTL3 in mediating the SNHG7 axis in MNNG-induced GC. RIP-PCR and m6A-IP-qPCR were used to examine the molecular mechanism underlying the METTL3/m6A/SNHG7 axis in MNNG-induced GC. A METTL3 knockout mice model was constructed and exposed by MNNG. Western blot analysis, IHC analysis, and RT-qPCR were used to measure the expression of METTL3, SNHG7, and EMT markers. In this study, we demonstrated that in MNNG-induced GC tumorigenesis, the m6A modification regulator METTL3 facilitates cellular EMT and biological functions through the m6A/SNHG7 axis using in vitro and in vivo models. In conclusion, our study provides novel insights into critical epigenetic molecular events vital to MNNG-induced gastric carcinogenesis. These findings suggest the potential therapeutic targets of METTL3 for GC treatment.
作为化学致癌物的典型代表，N-甲基-N'-硝基-N-亚硝基胍（MNNG）与胃癌（GC）的发生密切相关，其中N6-甲基腺苷（m6A）RNA甲基化被认为是一个关键的表观遗传事件。在我们之前的研究中，我们发现与体外对照细胞相比，在MNNG处理的恶性GES-1细胞（MC细胞）中，甲基转移酶METTL3介导的m6A修饰上调，并且长链非编码RNA SNHG7是METTL3的下游靶点。然而，METTL3在MNNG诱导的胃癌中介导SNHG7轴的功能作用仍不清楚。在本研究中，我们继续探究METTL3在MNNG诱导的胃癌中介导SNHG7轴的功能作用。采用RNA免疫沉淀-聚合酶链反应（RIP-PCR）和m6A免疫沉淀-定量聚合酶链反应（m6A-IP-qPCR）来研究MNNG诱导的胃癌中METTL3/m6A/SNHG7轴的分子机制。构建了METTL3基因敲除小鼠模型并给予MNNG处理。采用蛋白质免疫印迹分析、免疫组化分析和逆转录-定量聚合酶链反应来检测METTL3、SNHG7和上皮-间质转化（EMT）标志物的表达。在本研究中，我们证明在MNNG诱导的胃癌发生过程中，m6A修饰调节因子METTL3通过m6A/SNHG7轴利用体外和体内模型促进细胞EMT和生物学功能。总之，我们的研究为MNNG诱导的胃癌发生中关键的表观遗传分子事件提供了新的见解。这些发现提示了METTL3作为胃癌治疗潜在靶点的可能性。
