Long non-coding RNA MAGEA4-AS1 binding to p53 enhances MK2 signaling pathway and promotes the proliferation and metastasis of oral squamous cell carcinoma

IF 3.9 4区生物学 Q1 GENETICS & HEREDITY

Functional & Integrative Genomics Pub Date : 2024-09-09 DOI:10.1007/s10142-024-01436-6

Xiaoxiao Wei, Zhangfu Li, Heng Zheng, Xiaolian Li, Yuntao Lin, Hongyu Yang, Yuehong Shen

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Abstract

Long non-coding RNAs (lncRNAs) regulate the occurrence, development and progression of oral squamous cell carcinoma (OSCC). We elucidated the expression features of MAGEA4-AS1 in patients with OSCC and its activity as an OSCC biomarker. Furthermore, the impact of up-regulation of MAGEA4-AS1 on the cellular behaviors (proliferation, migration and invasion) of OSCC cells and intrinsic signal mechanisms were evaluated. Firstly, we analyzed MAGEA4-AS1 expression data in The Cancer Genome Atlas (TCGA) OSCC using a bioinformatics approach and in 45 pairs of OSCC tissues using qPCR. Then CCK-8, ethynyl deoxyuridine, colony formation, transwell and wound healing assays were conducted to assess changes in the cell proliferation, migration and invasion protential of shMAGEA4-AS1 HSC3 and CAL27 cells. The RNA sequence of MAGEA4-AS1 was identified using the rapid amplification of cDNA ends (RACE) assay. And whole-transcriptome sequencing was used to identify MAGEA4-AS1 affected genes. Additionally, dual-luciferase reporter system, RNA-binding protein immunoprecipitation (RIP), and rescue experiments were performed to clarify the role of the MAGEA4-AS1-p53-MK2 signaling pathway. As results, we found MAGEA4-AS1 was up-regulated in OSCC tissues. We identified a 418 nucleotides length of the MAGEA4-AS1 transcript and it primarily located in the cell nucleus. MAGEA4-AS1 stable knockdown weakened the proliferation, migration and invasion abilities of OSCC cells. Mechanistically, p53 protein was capable to activate MK2 gene transcription. RIP assay revealed an interaction between p53 and MAGEA4-AS1. MK2 up-regulation in MAGEA4-AS1 down-regulated OSCC cells restored MK2 and epithelial-to-mesenchymal transition related proteins’ expression levels. In conclusion, MAGEA4-AS1-p53 complexes bind to MK2 promoter, enhancing the transcription of MK2 and activating the downstream signaling pathways, consequently promoting the proliferation and metastasis of OSCC cells. MAGEA4-AS1 may serve as a diagnostic marker and therapeutic target for OSCC patients.

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长非编码 RNA MAGEA4-AS1 与 p53 结合可增强 MK2 信号通路，促进口腔鳞状细胞癌的增殖和转移。

长非编码 RNA（lncRNA）调控着口腔鳞状细胞癌（OSCC）的发生、发展和恶化。我们阐明了MAGEA4-AS1在OSCC患者中的表达特征及其作为OSCC生物标志物的活性。此外，我们还评估了MAGEA4-AS1上调对OSCC细胞行为（增殖、迁移和侵袭）的影响以及内在信号机制。首先，我们采用生物信息学方法分析了癌症基因组图谱（TCGA）OSCC中MAGEA4-AS1的表达数据，并采用qPCR方法分析了45对OSCC组织中MAGEA4-AS1的表达数据。然后进行了CCK-8、乙炔基脱氧尿苷、集落形成、跨孔和伤口愈合试验，以评估shMAGEA4-AS1 HSC3和CAL27细胞增殖、迁移和侵袭能力的变化。利用 cDNA末端快速扩增（RACE）实验确定了 MAGEA4-AS1 的 RNA 序列。全转录组测序用于鉴定受 MAGEA4-AS1 影响的基因。此外，还进行了双荧光素酶报告系统、RNA结合蛋白免疫沉淀（RIP）和拯救实验，以明确MAGEA4-AS1-p53-MK2信号通路的作用。结果发现，MAGEA4-AS1在OSCC组织中上调。我们发现MAGEA4-AS1转录本长度为418个核苷酸，主要位于细胞核内。稳定敲除MAGEA4-AS1会削弱OSCC细胞的增殖、迁移和侵袭能力。从机制上讲，p53 蛋白能够激活 MK2 基因的转录。RIP试验显示，p53与MAGEA4-AS1之间存在相互作用。在 MAGEA4-AS1 下调的 OSCC 细胞中上调 MK2 可恢复 MK2 和上皮-间质转化相关蛋白的表达水平。总之，MAGEA4-AS1-p53复合物与MK2启动子结合，增强了MK2的转录，激活了下游信号通路，从而促进了OSCC细胞的增殖和转移。MAGEA4-AS1可作为OSCC患者的诊断标志物和治疗靶点。

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来源期刊

Functional & Integrative Genomics 生物-遗传学

CiteScore

3.50

自引率

3.40%

发文量

审稿时长

2 months

期刊介绍： Functional & Integrative Genomics is devoted to large-scale studies of genomes and their functions, including systems analyses of biological processes. The journal will provide the research community an integrated platform where researchers can share, review and discuss their findings on important biological questions that will ultimately enable us to answer the fundamental question: How do genomes work?