胃癌是消化系统最常见的恶性肿瘤之一，多数患者发现时已处于晚期，预后不佳。外科手术及化学治疗（化疗）仍是目前胃癌的主要治疗方式。N6-甲基腺嘌呤（N6-methyladenosine，m6A）是近年来肿瘤研究的热点。m6A作为真核生物中最常见的RNA修饰形式，可以调控RNA循环的各个阶段，包括RNA剪接、加工、降解和翻译等，从而调控RNA的表达和功能，在细胞分化、发育和代谢等各个环节中发挥关键作用。m6A去甲基化酶可去除RNA上的甲基基团，确保m6A甲基化是一个动态的可逆的过程。作为m6A甲基化过程的关键酶，m6A去甲基化酶——脂肪和肥胖相关蛋白（fat mass and obesity-associated protein，FTO）、AlkB同系物5（AlkB homolog 5，ALKBH5）、ALKBH3的失调能通过多种机制调控胃癌的演进过程，与胃癌的发生发展密切相关。m6A去甲基化酶通过调节信号通路，改变胃癌细胞的增殖和侵袭能力，影响胃癌对化疗药物的耐药性，参与调控胃癌的免疫应答及线粒体代谢，从而影响胃癌细胞的生长，有望成为一个全新的治疗靶点。该文综述了m6A去甲基化酶参与胃癌发生发展的分子机制，以及其表达和功能与胃癌生物学特性的关系，旨在为胃癌的早期诊断和靶向治疗提供新的研究思路。
关键词：N6-甲基腺嘌呤
;
脂肪和肥胖相关蛋白
;
ALKBH5
;
ALKBH3
;
胃癌
Abstract
Gastric cancer (GC) is one of the most common malignancies in the digestive system. Many patients are found in advanced stage and have a poor prognosis. Surgery and chemotherapy remain the main treatments for gastric cancer. N6-methyladenosine (m6A) is a hot topic in tumor research in recent years. As the most common form of RNA modification in eukaryotes, m6A can regulate various stages of the RNA cycle, including RNA splicing, processing, degradation, and translation, thereby regulating RNA expression and function, playing a critical role in various pathways such as cell differentiation, development, and metabolism. The m6A demethylase can remove methyl groups on RNA, ensuring that m6A methylation is a dynamic and reversible process. As a key enzyme in the m6A methylation process, the imbalance of m6A demethylases fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5) and ALKBH3 regulate the progression of gastric cancer through various mechanisms, which is closely related to the occurrence and development of gastric cancer. These m6A demethylases regulate the signaling pathway, alter the proliferation and invasion ability of gastric cancer cells, affect its resistance to chemotherapy drugs, participate in regulating the immune response and mitochondrial metabolism of gastric cancer, and affect the growth of gastric cancer cells. They are expected to become a novel therapeutic target. This article comprehensively summarizes the molecular mechanism of m6A demethylase involved in the occurrence and development of gastric cancer, and the relationship between its expression and function, and biological characteristics of m6A demethylase were reviewed, aiming to provide new research ideas for early diagnosis and targeted treatment of gastric cancer.
Keywords：N6-methyladenosine (m6A)
;
fat mass and obesity-associated protein (FTO)
;
AlkB homolog 5 (ALKBH5)
;
ALKBH3
;
gastric cancer
JIANG Shuang, YU Jiwei. Progress of research on m6A demethylases in gastric cancer. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2024, 44(2): 271-277 doi:10.3969/j.issn.1674-8115.2024.02.014
N6-甲基腺嘌呤（N6-methyladenosine，m6A）甲基化修饰是真核生物中最常见的内部化学修饰，在真核生物的RNA中广泛存在，调控着RNA循环的各个阶段。而m6A的失调与肿瘤的发生密切相关。m6A甲基化修饰主要受三大类酶调控，包括甲基转移酶（writer）、去甲基化酶（eraser，也称m6A“擦除酶”），以及m6A阅读蛋白（reader）。m6A甲基化修饰可以通过去甲基化酶去除，因此该甲基化修饰过程是可逆和动态的。脂肪和肥胖相关蛋白（fat mass and obesity-associated protein，FTO）作为第一个被发现的m6A去甲基化酶，证明了信使RNA（messenger RNA，mRNA）中的表观遗传修饰也是动态和可逆的，这一发现振兴了RNA表观遗传学研究领域。鉴于m6A去甲基化酶对诸多恶性肿瘤的发病起到关键作用，目前已有针对去甲基化酶的小分子抑制剂用于恶性肿瘤的治疗。在当前所有恶性肿瘤中，胃癌发病率位列全球第五位，死亡率位列第四位［1］。随着内镜技术的进步，越来越多的胃部早期病变得到了妥善的治疗，胃癌发病率呈现一定的下降趋势，但晚期患者仍然面临着无法手术的风险，病死率非常高。虽然胃癌的综合治疗历经了化学治疗（化疗）、靶向治疗和免疫治疗3次革命性突破，但进展期胃癌仍无有效的治疗手段。目前的研究显示，通过靶向m6A去甲基化酶抑制肿瘤生长、增强免疫疗效和减少细胞耐药性均取得了积极的治疗意义。因此本文就m6A去甲基化酶在胃癌发生和在癌症干细胞的分子机制、微环境调节、免疫和代谢中的作用，以及靶向去甲基化酶用于胃癌治疗潜力的最新研究进展作一综述。
JIANG Shuang proposed the idea, collected the literature and completed the writing. YU Jiwei was in charge of the content design and revision of the article. Both authors have read the last version of paper and consented for submission.
利益冲突声明
2位作者声明不存在利益冲突。
COMPETING INTERESTS
Both authors disclose no relevant conflict of interests.
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... N6-甲基腺嘌呤（N6-methyladenosine，m6A）甲基化修饰是真核生物中最常见的内部化学修饰，在真核生物的RNA中广泛存在，调控着RNA循环的各个阶段.而m6A的失调与肿瘤的发生密切相关.m6A甲基化修饰主要受三大类酶调控，包括甲基转移酶（writer）、去甲基化酶（eraser，也称m6A“擦除酶”），以及m6A阅读蛋白（reader）.m6A甲基化修饰可以通过去甲基化酶去除，因此该甲基化修饰过程是可逆和动态的.脂肪和肥胖相关蛋白（fat mass and obesity-associated protein，FTO）作为第一个被发现的m6A去甲基化酶，证明了信使RNA（messenger RNA，mRNA）中的表观遗传修饰也是动态和可逆的，这一发现振兴了RNA表观遗传学研究领域.鉴于m6A去甲基化酶对诸多恶性肿瘤的发病起到关键作用，目前已有针对去甲基化酶的小分子抑制剂用于恶性肿瘤的治疗.在当前所有恶性肿瘤中，胃癌发病率位列全球第五位，死亡率位列第四位［1］.随着内镜技术的进步，越来越多的胃部早期病变得到了妥善的治疗，胃癌发病率呈现一定的下降趋势，但晚期患者仍然面临着无法手术的风险，病死率非常高.虽然胃癌的综合治疗历经了化学治疗（化疗）、靶向治疗和免疫治疗3次革命性突破，但进展期胃癌仍无有效的治疗手段.目前的研究显示，通过靶向m6A去甲基化酶抑制肿瘤生长、增强免疫疗效和减少细胞耐药性均取得了积极的治疗意义.因此本文就m6A去甲基化酶在胃癌发生和在癌症干细胞的分子机制、微环境调节、免疫和代谢中的作用，以及靶向去甲基化酶用于胃癌治疗潜力的最新研究进展作一综述. ...
