FTO downregulation-mediated m6A modification resulting in enhanced hepatocellular carcinoma invasion

作者：Cheng Zhou, Yong Zhang, Shi-Ming Shi, Dan Yin, Xuedong Li, Ying–Hong Shi, Jian Zhou, Zheng Wang, Qing Chen · 发表于：Cell & Bioscience · 年份：2025 · DOI：10.1186/s13578-025-01395-w · 被引用次数：12 · 研究领域：RNA modifications and cancer、Metalloenzymes and iron-sulfur proteins、Cancer, Hypoxia, and Metabolism

BACKGROUND: Dysregulation of N6-methyladenosine (m6A) modifications has been implicated in various cancers, including hepatocellular carcinoma (HCC). This study aimed to elucidate the role of m6A modifications in HCC prognosis and the molecular mechanisms involved, particularly focusing on the demethylase FTO. METHODS: We analyzed m6A expression in a cohort of 323 HCC patients using immunohistochemical (IHC) staining. The expression of m6A-related genes (FTO, ALKBH5, METTL3, METTL14) was evaluated by qRT-PCR in 120 paired HCC tissues. Further, we established HCC cell lines with altered FTO expression to assess its impact on cell proliferation, invasion, and metastasis through various in vitro assays and in vivo orthotopic HCC mouse models. Statistical analyses included Pearson chi-square test, Kaplan-Meier survival analysis, and both univariate and multivariate Cox regression analyses. RESULTS: IHC staining revealed elevated m6A levels in HCC tissues compared to adjacent non-tumorous tissues, with 57.3% of HCC patients showing increased m6A expression. High m6A levels were correlated with poorer overall survival (OS) and recurrence-free survival (RFS) rates. FTO, a demethylase, was significantly downregulated in HCC tissues and cell lines, particularly in highly metastatic lines. Overexpression of FTO in HCC cells reduced proliferation, migration, and invasion, whereas FTO knockdown had the opposite effect. In vivo, FTO overexpression decreased tumor growth and metastasis. RN...