Department of Gastrointestinal Surgery, Meizhou People's Hospital, Meizhou, Guangdong, 514089, China.
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.
Biomed Pharmacother. 2021 Jan;133:111075. doi: 10.1016/j.biopha.2020.111075. Epub 2020 Dec 9.
N-methyladenosine (mA) is one of the most abundant messenger RNAs modification. Increasing evidence illustrates its critical role on gastric cancer. Here, present research focuses on the potential function of mA methyltransferase Wilms' tumour 1-associated protein (WTAP) in gastric cancer tumorigenesis. Firstly, mA immunoprecipitation sequencing analysis (MeRIP-Seq) analysis demonstrated the mA profile in gastric cancer cells. Both WTAP and the mA expression were up-regulated in gastric cancer tissue and cells. The high-expression of WTAP was closely correlated with poor prognosis of gastric cancer patients. Functional experiments illustrated that WTAP promoted the proliferation and glycolytic capacity (glucose uptake, lactate production and extracellular acidification rate) in vitro, and the knockdown of WTAP suppressed the tumor growth in vivo. Mechanistically, HK2 was identified to be the target of WTAP using MeRIP-Seq and MeRIP-qPCR. WTAP enhanced the stability of HK2 mRNA through binding with the 3'-UTR mA site. In conclusion, our results demonstrate the oncogenic role of WTAP and its mA-mediated regulation on gastric cancer Warburg effect, providing a novel approach and therapeutic target in gastric cancer.
N6-甲基腺苷（m6A）是最丰富的信使 RNA 修饰之一。越来越多的证据表明它在胃癌中起着关键作用。在这里，目前的研究集中在甲基转移酶 Wilms 瘤 1 相关蛋白（WTAP）在胃癌发生中的潜在功能。首先，mA 免疫沉淀测序分析（MeRIP-Seq）分析表明了胃癌细胞中的 mA 图谱。WTAP 和 mA 的表达在胃癌组织和细胞中均上调。WTAP 的高表达与胃癌患者的预后不良密切相关。功能实验表明，WTAP 促进了体外的增殖和糖酵解能力（葡萄糖摄取、乳酸生成和细胞外酸化率），而 WTAP 的敲低则抑制了体内的肿瘤生长。从机制上讲，使用 MeRIP-Seq 和 MeRIP-qPCR 鉴定 HK2 是 WTAP 的靶标。WTAP 通过与 3'-UTR mA 位点结合增强了 HK2 mRNA 的稳定性。总之，我们的结果表明 WTAP 具有致癌作用及其对胃癌瓦博格效应的 mA 介导调节，为胃癌提供了新的治疗方法和靶点。
