The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics and Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Department of Pathology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Int J Biol Sci. 2024 Jan 1;20(1):331-346. doi: 10.7150/ijbs.82316. eCollection 2024.
5-Methylcytosine (m5C) is one of the most ubiquitous modifications of mRNA and contributes to cancer pathogenesis. Aly/REF export factor (ALYREF), an m5C reader, is associated with the prognosis of liver hepatocellular carcinoma (LIHC). However, the effects of ALYREF on the progression of LIHC and the underlying molecular mechanisms remains elusive. Through an analysis of an online database and 3 independent LIHC cohorts, we found that ALYREF was markedly elevated in human liver cancer tissues and was significantly correlated with LIHC clinicopathological parameters, including Ki67 cell rate, high-grade TNM stage, and poor prognosis. Several experiments were conducted to investigate the molecular basis and functional role of ALYREF-related progression in this study. ALYREF could enhance LIHC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) and tumor formation . Mechanistically, ALYREF promoted the progression of human LIHC through EGFR pathways. Furthermore, ALYREF could directly bind to the m5C modification site of EGFR 3' untranslated region (3' UTR) to stabilize EGFR mRNA. Collectively, ALYREF played a crucial oncogenic role in LIHC via the stabilization of EGFR mRNA and subsequent activation of the STAT3 signaling pathway. Our results may help to elucidate the potential mechanisms of ALYREF-induced m5C modification in the progression of human LIHC.
5- 甲基胞嘧啶（m5C）是 mRNA 中最普遍的修饰之一，有助于癌症的发病机制。Aly/REF 输出因子（ALYREF）是一种 m5C 读码器，与肝癌（LIHC）的预后相关。然而，ALYREF 对 LIHC 进展的影响及其潜在的分子机制仍不清楚。通过对在线数据库和 3 个独立的 LIHC 队列的分析，我们发现在人类肝癌组织中，ALYREF 明显升高，并且与 LIHC 的临床病理参数显著相关，包括 Ki67 细胞率、高级别 TNM 分期和不良预后。在本研究中进行了几项实验来研究 ALYREF 相关进展的分子基础和功能作用。ALYREF 可以增强 LIHC 细胞的增殖、迁移、侵袭和上皮-间充质转化（EMT）和肿瘤形成。从机制上讲，ALYREF 通过 EGFR 途径促进了人类 LIHC 的进展。此外，ALYREF 可以直接结合 EGFR 3' 非翻译区（3'UTR）的 m5C 修饰位点，稳定 EGFR mRNA。总之，ALYREF 通过稳定 EGFR mRNA 并随后激活 STAT3 信号通路，在 LIHC 中发挥关键的致癌作用。我们的研究结果可能有助于阐明 ALYREF 诱导的 m5C 修饰在人类 LIHC 进展中的潜在机制。
