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m6A mRNA methylation regulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to promote proliferation and tumor formation in endometrial cancer
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2022-08-15 , DOI: 10.1007/s10565-022-09751-z
Peng Ruan 1 , Shujun Wang 2 , Chaoyi Yang 2 , Xiaohui Huang 2 , Pengxing Sun 2 , Aili Tan 2
Affiliation  

N6-methyladenosine (m6A) mRNA methylation has been considered a gene modulatory mechanism involved in disease progression and carcinogenesis. Herein, we aimed to explore the specific mechanism of m6A mRNA methylation in endometrial cancer. RT-qPCR was implemented to test the clinical correlation between m6A methylation and endometrial cancer. Bioinformatics analysis was performed to screen the genes related to endometrial cancer, and SRAMP was utilized for the prediction of m6A targets. Western blot assay and MeRIP-qPCR experiments were conducted to verify the effect of m6A methylation on the candidate genes and the signaling pathways involved in the occurrence of endometrial cancer. m6A-seq, RT-qPCR, and polysome profiling were used to confirm the mechanisms of m6A methylation in modulating related genes and pathways. The levels of m6A methylation, METTL3, and IGFBP4 were reduced in tumor tissues of patients with endometrial cancer, and SRAMP analysis confirmed that IGFBP4 and PAPPA had m6A methylation sites. Reduced m6A methylation promoted endometrial cancer cell progression and tumor formation in vivo. m6A methylation of RNA in endometrial cancer cells directly modulated IGFBP4 and PAPPA expression. m6A methylation regulated the PAPPA/IGFBP4 axis, thereby influencing endometrial cancer through the NF-κB and ERK signaling pathways. Knockdown of PAPPA or overexpression of IGFBP4 in endometrial cancer cells partially reduced disease progression caused by reduced m6A methylation. This research suggests that m6A mRNA methylation modulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to induce cell proliferation and tumor formation in endometrial cancer.

Graphical abstract

1. METTL3 expressed modestly and m6A methylation of IGFBP4 and PAPPA mRNAs decreased in endometrial cancer;

2. YTHDF1-mediated IGFBP4 translation was reduced in HEC-1-A and AN3CA cells, and YTHDF2-mediated PAPPA mRNA degradation was blunted but its protein expression increased;

3. Increased PAPPA and reduced IGFBP4 activated IGF1-induced ERK, AKT, and NF-κB pathways by binding IGFR, thereby promoting cancer cell malignancy.



中文翻译:

m6A mRNA甲基化通过PAPPA/IGFBP4轴调节ERK/NF-κB/AKT信号通路促进子宫内膜癌增殖和肿瘤形成

N6-甲基腺苷 (m 6 A) mRNA 甲基化被认为是参与疾病进展和癌变的基因调节机制。本论文旨在探讨m 6 A mRNA甲基化在子宫内膜癌中的具体机制。采用RT-qPCR来测试m 6 A甲基化与子宫内膜癌之间的临床相关性。通过生物信息学分析筛选子宫内膜癌相关基因,并利用SRAMP预测m 6 A靶点。通过Western blot检测和MeRIP-qPCR实验验证m 6 A甲基化对子宫内膜癌发生相关候选基因及信号通路的影响。m 6 A-seq、RT-qPCR 和多核糖体分析用于确认 m 6 A 甲基化调节相关基因和通路的机制。子宫内膜癌患者肿瘤组织中m 6 A甲基化、METTL3和IGFBP4水平降低,SRAMP分析证实IGFBP4和PAPPA存在m 6 A甲基化位点。m6A甲基化减少促进子宫内膜癌细胞进展和体内肿瘤形成m 6子宫内膜癌细胞中 RNA 的甲基化直接调节 IGFBP4 和 PAPPA 的表达。m 6 A 甲基化调节 PAPPA/IGFBP4 轴,从而通过 NF-κB 和 ERK 信号通路影响子宫内膜癌。子宫内膜癌细胞中 PAPPA 的敲低或 IGFBP4 的过度表达部分减缓了 m 6 A 甲基化减少引起的疾病进展。这项研究表明,m 6 A mRNA 甲基化通过 PAPPA/IGFBP4 轴调节 ERK/NF-κB/AKT 信号通路,从而诱导子宫内膜癌中的细胞增殖和肿瘤形成。

图形概要

1. METTL3在子宫内膜癌中适度表达,IGFBP4和PAPPA mRNA的m 6 A甲基化降低;

2. HEC-1-A和AN3CA细胞中YTHDF1介导的IGFBP4翻译减少,YTHDF2介导的PAPPA mRNA降解减弱,但其蛋白表达增加;

3.增加PAPPA和减少IGFBP4通过结合IGFR激活IGF1诱导的ERK、AKT和NF-κB通路,从而促进癌细胞恶性。

更新日期:2022-08-16
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