NAT10 promotes gastric cancer progression by enhancing the N4-acetylcytidine modification of TNC mRNA.

IF 3.1 2区医学 Q3 IMMUNOLOGY

Infectious Agents and Cancer Pub Date : 2025-03-29 DOI:10.1186/s13027-025-00650-6

Yu Chen, Jinzhou Wang, Jiuhua Xu, Ruilong Kou, Bin Lan, Zhiwei Qin

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引用次数: 0

Abstract

Background: Gastric cancer (GC) is a very aggressive malignant tumor of the digestive system. Previous studies have shown that N-acetyltransferase 10 (NAT10) can regulate the N4-acetylcytidine (ac4C) modification of downstream mRNAs through certain pathways to promote the progression of various tumors. However, reports on the regulatory effects of NAT10 on GC are rare. This study aimed to explore the potential mechanism by which NAT10 regulated GC progression.

Methods: Clinical samples were used to study the correlation between NAT10 expression and poor prognosis in patients with GC by univariate analysis and multivariate analysis. In vitro and in vivo assays were performed to assess the effects of NAT10 and Tenascin C (TNC) on the malignant biological behaviors of GC cells. Acetylated RNA immunoprecipitation sequencing was conducted to explore the role of NAT10 in ac4C modification in GC. mRNA stability and translation efficiency assays were performed to investigate the effect of changes in NAT10 expression on its target TNC.

Results: Analysis of clinical samples revealed that NAT10 expression was abnormally elevated and positively correlated with TNC expression in GC, and increased NAT10 expression led to poor overall survival. In vitro and in vivo experiments revealed that high NAT10 expression promoted the invasive and proliferative capacity of GC cells. Rescue experiments suggested that TNC played an important role in the above process. Mechanistically, the acetylation-based RNA immunoprecipitation sequencing and acetylated RNA immunoprecipitation qPCR results indicated that NAT10 regulated the level of ac4C modification by binding to specific regions in TNC mRNA, increasing mRNA stability and translation, upregulating TNC expression, further activating the TNC/Akt/TGF-β1 positive feedback loop.

Conclusions: In summary, our results reveal that NAT10 plays a critical role in GC development by affecting TNC mRNA stability and translation efficiency, which ultimately activates the TNC/Akt/TGF-β1 positive feedback loop. This study is expected to provide a novel target and theoretical basis for improving the diagnosis and treatment of GC.

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背景：胃癌（GC）是一种侵袭性很强的消化系统恶性肿瘤。以往的研究表明，N-乙酰转移酶 10（NAT10）可通过某些途径调控下游 mRNA 的 N4-乙酰胞苷（ac4C）修饰，从而促进各种肿瘤的进展。然而，有关 NAT10 对 GC 的调控作用的报道并不多见。本研究旨在探讨NAT10调控GC进展的潜在机制：方法：采用临床样本，通过单变量分析和多变量分析研究 NAT10 表达与 GC 患者不良预后之间的相关性。通过体外和体内试验评估 NAT10 和 Tenascin C (TNC) 对 GC 细胞恶性生物学行为的影响。进行了乙酰化RNA免疫沉淀测序，以探讨NAT10在GC中的ac4C修饰中的作用；进行了mRNA稳定性和翻译效率测定，以研究NAT10表达的变化对其靶标TNC的影响：结果：对临床样本的分析表明，NAT10在GC中的表达异常升高，且与TNC的表达呈正相关，NAT10表达的升高会导致总生存率降低。体外和体内实验显示，NAT10的高表达促进了GC细胞的侵袭和增殖能力。拯救实验表明，TNC 在上述过程中发挥了重要作用。从机理上讲，基于乙酰化的RNA免疫沉淀测序和乙酰化RNA免疫沉淀qPCR结果表明，NAT10通过与TNC mRNA中的特定区域结合来调控ac4C修饰水平，增加mRNA的稳定性和翻译，上调TNC的表达，进一步激活TNC/Akt/TGF-β1正反馈环：综上所述，我们的研究结果表明，NAT10通过影响TNC mRNA的稳定性和翻译效率，最终激活TNC/Akt/TGF-β1正反馈环，从而在GC的发育过程中发挥关键作用。这项研究有望为改善 GC 的诊断和治疗提供新的靶点和理论依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Infectious Agents and Cancer ONCOLOGY-IMMUNOLOGY

CiteScore

5.80

自引率

2.70%

发文量

期刊介绍： Infectious Agents and Cancer is an open access, peer-reviewed online journal that encompasses all aspects of basic, clinical, epidemiological and translational research providing an insight into the association between chronic infections and cancer. The journal welcomes submissions in the pathogen-related cancer areas and other related topics, in particular: • HPV and anogenital cancers, as well as head and neck cancers; • EBV and Burkitt lymphoma; • HCV/HBV and hepatocellular carcinoma as well as lymphoproliferative diseases; • HHV8 and Kaposi sarcoma; • HTLV and leukemia; • Cancers in Low- and Middle-income countries. The link between infection and cancer has become well established over the past 50 years, and infection-associated cancer contribute up to 16% of cancers in developed countries and 33% in less developed countries. Preventive vaccines have been developed for only two cancer-causing viruses, highlighting both the opportunity to prevent infection-associated cancers by vaccination and the gaps that remain before vaccines can be developed for other cancer-causing agents. These gaps are due to incomplete understanding of the basic biology, natural history, epidemiology of many of the pathogens that cause cancer, the mechanisms they exploit to cause cancer, and how to interrupt progression to cancer in human populations. Early diagnosis or identification of lesions at high risk of progression represent the current most critical research area of the field supported by recent advances in genomics and proteomics technologies.