m6A 介导的通过 p53/Line-1 信号通路调控口腔鳞状细胞癌的发展。

m6A-Mediated Regulates the Development of Oral Squamous Cell Carcinoma through p53/Line-1 Signaling.

机构信息

Department of Stomatology, the First Affiliated Hospital of Hunan University of Chinese Medicine, 410021 Changsha, Hunan, China.

Science and Technology Department, Hunan University of Chinese Medicine, 410208 Changsha, Hunan, China.

出版信息

Front Biosci (Landmark Ed). 2024 Jul 19;29(7):257. doi: 10.31083/j.fbl2907257.

DOI:10.31083/j.fbl2907257

PMID:39082352

Abstract

BACKGROUND

The importance of N6-methyladenosine (m6A) modification in tumorigenesis and progression have been highlighted. This study aimed to investigate the modification of insulin receptor substrate 1 () by m6A and its role in oral squamous cell carcinoma (OSCC).

METHODS

Bioinformatics was employed to predict differential genes related to epithelial-mesenchymal transition (EMT) in OSCC. Seventeen pairs of OSCC and paracancerous tissue samples were collected. The impact of IRS1 on OSCC cell growth and EMT was evaluated. The fluctuations in enrichment and the involvement of p53/Line-1 were investigated.

RESULTS

IRS1 was highly expressed in OSCC. IRS1 silencing decreased OSCC cell proliferation and increased apoptosis. IRS1 silencing hindered EMT by regulating related markers. IRS1 silencing upregulated p53 and downregulated Line-1 ORF1p. The p53 inhibition reversed the effects of IRS1 silencing and induced EMT in OSCC cells. Furthermore, the m6A modification of was increased in OSCC cells. IRS1 were positively regulated by the m6A regulators methyltransferase-like 14 (METTL14) and YTH domain-containing protein 1 (YTHDC1). IRS1 bound to YTHDC1, and YTHDC1 knockdown inhibited the IRS1 nuclear export. The obesity-associated protein (FTO) negatively regulated IRS1, and FTO overexpression reversed the IRS1-induced OSCC tumor growth.

CONCLUSIONS

m6A methylation-mediated regulated EMT in OSCC through p53/Line-1. These findings provide potential therapeutic strategies for managing OSCC.

摘要

背景

N6-甲基腺苷（m6A）修饰在肿瘤发生和进展中的重要性已得到强调。本研究旨在探讨胰岛素受体底物 1（IRS1）的 m6A 修饰及其在口腔鳞状细胞癌（OSCC）中的作用。

方法

采用生物信息学方法预测 OSCC 中与上皮-间充质转化（EMT）相关的差异基因。收集 17 对 OSCC 及癌旁组织样本。评估 IRS1 对 OSCC 细胞生长和 EMT 的影响。研究了富集的波动和 p53/Line-1 的参与情况。

结果

IRS1 在 OSCC 中高表达。IRS1 沉默降低了 OSCC 细胞的增殖，增加了细胞凋亡。IRS1 沉默通过调节相关标志物抑制 EMT。IRS1 沉默上调了 p53，下调了 Line-1 ORF1p。p53 抑制逆转了 IRS1 沉默的作用，并诱导了 OSCC 细胞发生 EMT。此外，OSCC 细胞中的 IRS1 发生了 m6A 修饰。甲基转移酶样蛋白 14（METTL14）和 YTH 结构域包含蛋白 1（YTHDC1）等 m6A 调节因子正向调节 IRS1。IRS1 与 YTHDC1 结合，YTHDC1 敲低抑制了 IRS1 的核输出。肥胖相关蛋白（FTO）负向调节 IRS1，FTO 过表达逆转了 IRS1 诱导的 OSCC 肿瘤生长。