FTO-mediated m6A demethylation of SERPINE1 mRNA promotes tumor progression in hypopharyngeal squamous cell carcinoma.

IF 1.5 4区 医学 Q4 ONCOLOGY
Translational cancer research Pub Date : 2025-01-31 Epub Date: 2025-01-23 DOI:10.21037/tcr-2024-2507
Na Sa, Xuliang Liu, Dake Hao, Zhenghua Lv, Shengli Zhou, Linxue Yang, Shan Jiang, Jiajun Tian, Wei Xu
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引用次数: 0

Abstract

Background: The fat mass and obesity-associated protein (FTO) is implicated in various diseases and acts as a demethylase for the most abundant modification of mRNA, namely N6-methyladenosine (m6A) modification. It is known that FTO may play an oncogenic role or a tumor-suppressor role in different malignancies. The aim of this study was to investigate the functional roles of FTO in regulating biological processes related to hypopharyngeal squamous cell carcinoma (HSCC).

Methods: Using immunohistochemistry, quantitative real-time polymerase chain reaction (RT-qPCR), and Western blot analysis, we compared the expression levels of FTO in HSCC tissues to adjacent non-cancerous tissues. Furthermore, we evaluated the prognosis of patients with hypopharyngeal cancer in relation to FTO expression levels. In vitro, the Cell Counting Kit-8 (CCK8), wound healing assay, migration and invasion assays were used to identify roles of FTO in HSCC cells FaDu. Tumor xenografts in nude mice were used to disclose the effect of FTO in vivo. Then, transcriptome RNA sequencing (RNA-seq) assays were applied to screen for possible target genes. To confirm the specific site for modulating the expression of the target gene, we used the SRAMP database and methylated RNA immunoprecipitation PCR (MeRIP-PCR).

Results: The results showed that FTO was highly expressed in hypopharyngeal cancer tissues and was correlated with clinicopathology of patients. FTO promoted the proliferation, invasion and migration of hypopharyngeal cancer cells in vitro through its demethylase action. In vivo experiments showed that FTO promoted the growth of subcutaneously implanted tumors of hypopharyngeal cancer cells and their metastasis. Moreover, we revealed that FTO affected the malignant biological behavior of hypopharyngeal cancer cells by regulating the m6A modification level of SERPINE1 mRNA. FTO promoted epithelial-mesenchymal transformation (EMT) of hypopharyngeal cancer cells through the SERPINE1 signaling axis.

Conclusions: Our study highlighted the functional significance of the FTO/SERPINE1 axis in tumorigenesis of HSCC. Targeting FTO holds promise as a new therapeutic strategy for HSCC.

fto介导的SERPINE1 mRNA的m6A去甲基化促进下咽鳞状细胞癌的肿瘤进展。
背景:脂肪量和肥胖相关蛋白(FTO)与多种疾病有关,并作为mRNA最丰富修饰的去甲基化酶,即n6 -甲基腺苷(m6A)修饰。已知FTO可能在不同的恶性肿瘤中起致瘤作用或抑瘤作用。本研究的目的是探讨FTO在调节下咽鳞状细胞癌(HSCC)相关生物学过程中的功能作用。方法:采用免疫组织化学、实时定量聚合酶链反应(RT-qPCR)和Western blot分析,比较FTO在hsc组织与癌旁非癌组织中的表达水平。此外,我们评估了下咽癌患者的预后与FTO表达水平的关系。体外,采用细胞计数试剂盒-8 (CCK8)、伤口愈合试验、迁移和侵袭试验来鉴定FTO在hsc细胞FaDu中的作用。利用裸鼠肿瘤异种移植来揭示FTO在体内的作用。然后,应用转录组RNA测序(RNA-seq)方法筛选可能的靶基因。为了确定调控靶基因表达的特定位点,我们使用了SRAMP数据库和甲基化RNA免疫沉淀PCR (MeRIP-PCR)。结果:FTO在下咽癌组织中高表达,并与患者临床病理相关。FTO通过其去甲基化酶作用促进下咽癌细胞的体外增殖、侵袭和迁移。体内实验表明,FTO能促进下咽癌细胞皮下植入肿瘤的生长和转移。此外,我们发现FTO通过调节SERPINE1 mRNA的m6A修饰水平影响下咽癌细胞的恶性生物学行为。FTO通过SERPINE1信号轴促进下咽癌细胞的上皮-间质转化(EMT)。结论:我们的研究强调了FTO/SERPINE1轴在hsc肿瘤发生中的功能意义。靶向FTO有望成为治疗hsc的新策略。
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来源期刊
CiteScore
2.10
自引率
0.00%
发文量
252
期刊介绍: Translational Cancer Research (Transl Cancer Res TCR; Print ISSN: 2218-676X; Online ISSN 2219-6803; http://tcr.amegroups.com/) is an Open Access, peer-reviewed journal, indexed in Science Citation Index Expanded (SCIE). TCR publishes laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer; results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of cancer patients. The focus of TCR is original, peer-reviewed, science-based research that successfully advances clinical medicine toward the goal of improving patients'' quality of life. The editors and an international advisory group of scientists and clinician-scientists as well as other experts will hold TCR articles to the high-quality standards. We accept Original Articles as well as Review Articles, Editorials and Brief Articles.
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