Silencing of lncRNA LOC105376794 promotes migration, invasion, and Gefitinib resistance of lung adenocarcinoma cells with EGFR 19Del mutation by ATF4/CHOP axis and ERK phosphorylation.

IF 2 4区 医学 Q3 ONCOLOGY Neoplasma Pub Date : 2024-06-01 DOI:10.4149/neo_2024_230616N316
Wenjing Liu, Zhipeng Duan, Yefeng Wu, Rui Ma
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引用次数: 0

Abstract

Epidermal growth factor receptor (EGFR) gene exon 19 in-frame deletion (19del) and exon 21 L858R point mutation (21L858R mutation) are prevalent mutations in lung adenocarcinoma. Lung adenocarcinoma patients with 19del presented with a better prognosis than the 21L858R mutation under the same epidermal growth factor receptor tyrosine kinase inhibitor treatment. Our study aimed to uncover the expression of long non-coding RNA LOC105376794 between 19del and 21L858R mutation, and explore the mechanism that regulates cells' biological behavior and gefitinib sensitivity in lung adenocarcinoma cells with 19del. Transcriptome sequencing was conducted to identify differentially expressed lncRNAs between EGFR 19del and 21L858R mutation in serum through the DNBSEQ Platform. Protein-protein interaction network and Kyoto Encyclopedia of Genes and Genomes pathway were conducted to analyze the relationship between lncRNAs and mRNAs through STRING and Dr. TOM. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression of lncRNA LOC105376794 in serum and cells. Loss-of-function experiments were used to validate the biological function and gefitinib sensitivity of LOC105376794 in lung adenocarcinoma cells. Protein levels were detected by western blotting. Through transcriptome resequencing and RT-qPCR, we found the expression levels of LOC105376794 in serum were increased in the 19del group compared with the 21L858R mutation group. Inhibition of LOC105376794 promoted proliferation, migration and invasion, and reduced apoptosis of HCC827 and PC-9 cells. The low expression of LOC105376794 reduced gefitinib sensitivity in PC-9 cells. Mechanistically, we found that the knockdown of LOC105376794 suppressed activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP) signaling pathway and facilitated the expression of extracellular signal-regulated kinase 1/2 (ERK) phosphorylation. LOC105376794 altered cell biological behavior and gefitinib sensitivity of lung adenocarcinoma cells with 19del through the ATF4/CHOP signaling pathway and the expression of ERK phosphorylation. The results further illustrated the fact that lung adenocarcinoma patients with 19del presented with a more favorable clinical outcome and provided a theoretical basis for treatment strategy for lung adenocarcinoma patients with 19del.

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沉默lncRNA LOC105376794可通过ATF4/CHOP轴和ERK磷酸化促进表皮生长因子受体19Del突变的肺腺癌细胞的迁移、侵袭和吉非替尼耐药性。
表皮生长因子受体(EGFR)基因第19外显子框内缺失(19del)和第21外显子L858R点突变(21L858R突变)是肺腺癌的常见突变。在同样的表皮生长因子受体酪氨酸激酶抑制剂治疗下,19del突变的肺腺癌患者的预后比21L858R突变的患者好。我们的研究旨在揭示长非编码RNA LOC105376794在19del和21L858R突变之间的表达,并探索调节19del肺腺癌细胞生物学行为和吉非替尼敏感性的机制。通过DNBSEQ平台进行转录组测序,鉴定血清中表皮生长因子受体19del和21L858R突变之间差异表达的lncRNA。通过STRING和Dr. TOM进行蛋白-蛋白相互作用网络和京都基因组百科全书途径分析lncRNA与mRNA之间的关系。采用逆转录-定量聚合酶链反应(RT-qPCR)测定lncRNA LOC105376794在血清和细胞中的表达。功能缺失实验用于验证 LOC105376794 在肺腺癌细胞中的生物学功能和吉非替尼敏感性。蛋白水平通过蛋白印迹法检测。通过转录组重测序和 RT-qPCR,我们发现与 21L858R 突变组相比,19del 组血清中 LOC105376794 的表达水平升高。抑制 LOC105376794 可促进 HCC827 和 PC-9 细胞的增殖、迁移和侵袭,并减少其凋亡。LOC105376794的低表达降低了PC-9细胞对吉非替尼的敏感性。从机理上讲,我们发现LOC105376794的敲除抑制了激活转录因子4(ATF4)/C/EBP同源蛋白(CHOP)信号通路,促进了细胞外信号调节激酶1/2(ERK)磷酸化的表达。LOC105376794通过ATF4/CHOP信号通路和ERK磷酸化表达改变了19del肺腺癌细胞的生物学行为和吉非替尼敏感性。研究结果进一步说明,19del基因肺腺癌患者的临床预后更佳,为19del基因肺腺癌患者的治疗策略提供了理论依据。
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来源期刊
Neoplasma
Neoplasma 医学-肿瘤学
CiteScore
5.40
自引率
0.00%
发文量
238
审稿时长
3 months
期刊介绍: The journal Neoplasma publishes articles on experimental and clinical oncology and cancer epidemiology.
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