Kim Sang Yean, Ha Jin Woong, Na Min Jeong, Jeon Soyoung, Yoon Jung Hwan, Park Won Sang, Nam Suk Woo
Department of Pathology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Republic of Korea.
Functional RNomics Research Center, The Catholic University of Korea, Seocho-gu, Seoul, Republic of Korea.
Exp Mol Med. 2025 Jun 2. doi: 10.1038/s12276-025-01459-4.
Long noncoding RNA growth arrest-specific transcript 5 (GAS5) has been identified as a tumor suppressor due to its downregulation in several cancers. However, our comprehensive analyses revealed aberrant overexpression of GAS5 in various cancers, with a direct association with SMARCA4 in hepatocellular carcinoma (HCC). Differential expression analyses were conducted using publicly available transcriptome datasets. Functional studies of GAS5 and its downstream targets in HCC were performed via small interfering RNA-mediated knockdown in various HCC cell lines, in vivo xenograft mouse models and spontaneous liver cancer models in Ras-transgenic mice. Here we discover that METTL3-mediated N-methyladenosine modification promoted IGF2BP2 binding, stabilizing GAS5 in HCC. GAS5 expression was significantly upregulated in large cohort of patients with solid cancer, including HCC. Targeted disruption of GAS5 resulted in notable inhibition of growth and proliferation in HCC cells. Further analyses demonstrated that GAS5 enhanced in vitro tumorigenesis and metastatic potential of HCC cells. MicroRNA target prediction and functional validation indicated that GAS5 shared a miR-423-3p binding element with SMARCA4 messenger RNA, functioning as a competing endogenous RNA. This interaction was validated in vitro tumorigenesis assays and in vivo models. Moreover, a synergistic effect was observed with vehicle containing a small interfering RNA mixture targeting both GAS5 and SMARCA4 in these animal models. N-methyladenosine-mediated IGF2BP2 binding stabilizes GAS5, which functions as a competing endogenous RNA for miR-423-3p, thereby enhancing the translation of SMARCA4 messenger RNA. GAS5 acts as a crucial regulator of the oncogenic SMARCA4 in hepatocellular carcinogenesis, presenting a potential therapeutic target for the treatment of liver malignancies.
长链非编码RNA生长停滞特异性转录本5（GAS5）已被确定为一种肿瘤抑制因子，因为它在多种癌症中表达下调。然而，我们的综合分析显示，GAS5在各种癌症中异常过表达，在肝细胞癌（HCC）中与SMARCA4直接相关。使用公开可用的转录组数据集进行差异表达分析。通过小干扰RNA介导的敲低，在各种HCC细胞系、体内异种移植小鼠模型和Ras转基因小鼠的自发性肝癌模型中，对HCC中GAS5及其下游靶点进行了功能研究。在这里，我们发现METTL3介导的N-甲基腺苷修饰促进了IGF2BP2结合，从而在HCC中稳定了GAS5。在包括HCC在内的大量实体癌患者中，GAS5表达显著上调。靶向破坏GAS5导致HCC细胞的生长和增殖受到显著抑制。进一步分析表明，GAS5增强了HCC细胞的体外肿瘤发生和转移潜能。微小RNA靶标预测和功能验证表明，GAS5与SMARCA4信使RNA共享一个miR-423-3p结合元件，作为竞争性内源性RNA发挥作用。这种相互作用在体外肿瘤发生试验和体内模型中得到了验证。此外，在这些动物模型中，观察到含有靶向GAS5和SMARCA4的小干扰RNA混合物的载体具有协同作用。N-甲基腺苷介导的IGF2BP2结合稳定了GAS5，GAS5作为miR-423-3p的竞争性内源性RNA，从而增强了SMARCA4信使RNA的翻译。GAS5在肝细胞癌发生过程中作为致癌性SMARCA4的关键调节因子，为肝恶性肿瘤的治疗提供了一个潜在的治疗靶点。
