PDF(Pubmed)
Abstract：
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common malignant tumor in respiratory system. Methyltransferase-like 1 (METTL1) is a driver of m7G modification in mRNA. This study aimed to demonstrate the role of METTL1 in the proliferation, invasion and Gefitinib-resistance of LUAD.
METHODS: Public datasets were downloaded from the Gene Expression Profiling Interactive Analysis (GEPIA) and GSE31210 datasets. Malignant tumor phenotypes were tested in vitro and in vivo through biological function assays and nude mouse with xenograft tumors. RNA immunoprecipitation assays were conducted to determine the interaction between METTL1 protein and FOXM1 mRNA. Public transcriptional database, Chromatin immunoprecipitation and luciferase report assays were conducted to detect the downstream target of a transcriptional factor FOXM1. Half maximal inhibitory concentration (IC50) was calculated to evaluate the sensitivity to Gefitinib in LUAD cells.
RESULTS: The results showed that METTL1 was upregulated in LUAD, and the high expression of METTL1 was associated with unfavorable prognosis. Through the m7G-dependent manner, METTL1 improved the RNA stability of FOXM1, leading to the up-regulation of FOXM1. FOXM1 transcriptionally suppressed PTPN13 expression. The METTL1/FOXM1/PTPN13 axis reduced the sensitivity of LUAD cells to Gefitinib. Taken together, our data suggested that METTL1 plays oncogenic role in LUAD through inducing the m7G modification of FOXM1, therefore METTL1 probably is a new potential therapeutic target to counteract Gefitinib resistance in LUAD.
METHODS: Public datasets were downloaded from the Gene Expression Profiling Interactive Analysis (GEPIA) and GSE31210 datasets. Malignant tumor phenotypes were tested in vitro and in vivo through biological function assays and nude mouse with xenograft tumors. RNA immunoprecipitation assays were conducted to determine the interaction between METTL1 protein and FOXM1 mRNA. Public transcriptional database, Chromatin immunoprecipitation and luciferase report assays were conducted to detect the downstream target of a transcriptional factor FOXM1. Half maximal inhibitory concentration (IC50) was calculated to evaluate the sensitivity to Gefitinib in LUAD cells.
RESULTS: The results showed that METTL1 was upregulated in LUAD, and the high expression of METTL1 was associated with unfavorable prognosis. Through the m7G-dependent manner, METTL1 improved the RNA stability of FOXM1, leading to the up-regulation of FOXM1. FOXM1 transcriptionally suppressed PTPN13 expression. The METTL1/FOXM1/PTPN13 axis reduced the sensitivity of LUAD cells to Gefitinib. Taken together, our data suggested that METTL1 plays oncogenic role in LUAD through inducing the m7G modification of FOXM1, therefore METTL1 probably is a new potential therapeutic target to counteract Gefitinib resistance in LUAD.
摘要：
背景：肺腺癌（LUAD）是呼吸系统最常见的恶性肿瘤。甲基转移酶样1(METL1)是mRNA中m7G修饰的驱动因子。本研究旨在证明METTL1在细胞增殖中的作用,LUAD的侵袭和吉非替尼耐药。
方法：公共数据集从基因表达分析交互分析（GEPIA）和GSE31210数据集下载。通过生物学功能测定和具有异种移植肿瘤的裸鼠在体外和体内测试恶性肿瘤表型。进行RNA免疫沉淀测定以确定METTL1蛋白与FOXM1mRNA之间的相互作用。公共转录数据库，进行染色质免疫沉淀和荧光素酶报告测定以检测转录因子FOXM1的下游靶标。计算半数最大抑制浓度(IC50)以评估LUAD细胞中对吉非替尼的敏感性。
结果：结果显示，METTL1在LUAD中上调，METTL1的高表达与预后不良有关。通过m7G依赖的方式，METTL1提高了FOXM1的RNA稳定性，导致FOXM1的上调。FOXM1转录抑制PTPN13表达。METTL1/FOXM1/PTPN13轴降低了LUAD细胞对吉非替尼的敏感性。一起来看,我们的数据表明,METTL1通过诱导FOXM1的m7G修饰在LUAD中发挥致癌作用,因此METTL1可能是抵消LUAD吉非替尼耐药的新的潜在治疗靶点.
方法：公共数据集从基因表达分析交互分析（GEPIA）和GSE31210数据集下载。通过生物学功能测定和具有异种移植肿瘤的裸鼠在体外和体内测试恶性肿瘤表型。进行RNA免疫沉淀测定以确定METTL1蛋白与FOXM1mRNA之间的相互作用。公共转录数据库，进行染色质免疫沉淀和荧光素酶报告测定以检测转录因子FOXM1的下游靶标。计算半数最大抑制浓度(IC50)以评估LUAD细胞中对吉非替尼的敏感性。
结果：结果显示，METTL1在LUAD中上调，METTL1的高表达与预后不良有关。通过m7G依赖的方式，METTL1提高了FOXM1的RNA稳定性，导致FOXM1的上调。FOXM1转录抑制PTPN13表达。METTL1/FOXM1/PTPN13轴降低了LUAD细胞对吉非替尼的敏感性。一起来看,我们的数据表明,METTL1通过诱导FOXM1的m7G修饰在LUAD中发挥致癌作用,因此METTL1可能是抵消LUAD吉非替尼耐药的新的潜在治疗靶点.
