WTAP/IGF2BP3 Mediated m6A Modification of SOD2 mRNA Aggravates the Tumourigenesis of Colorectal Cancer

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-01-03 DOI:10.1002/jbt.70117

Chengfu Zhou, Meng Wang, Xinming Du, Lingkai Xue, Xiangchao Zhu, Xiaomin Li, Qiang Zhao

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引用次数: 0

Abstract

Wilms tumor 1-associated protein (WTAP) has been validated to be a crucial regulator in the tumorigenesis and advancement of diverse malignancies. This study intended to probe the impacts of WTAP on colorectal cancer (CRC) progression from the perspective of N6-methyladenosine (m6A) modification. The differential expression patterns of WTAP in clinical CRC samples and cultured cell lines were validated via qRT-PCR and western blot. Cell function tests were conducted with colony formation, transwell, and CCK-8. MeRIP-qPCR was conducted to identify the WTAP-mediated SOD2 (Superoxide dismutase 2) mRNA modification in CRC cells. Animal experiments were adopted to evaluate the function of WTAP in vivo. WTAP exhibited high expression pattern in CRC samples along with cells. Silencing of WTAP potently restrained the growth of CRC tumorigenesis in virto and in vivo. Mechanically, SOD2 was identified as an m6A target of WTAP. WTAP-mediated m6A modification of SOD2 mRNA elevated its stability in an IGF2BP3-dependent manner. Meanwhile, SOD2 overexpression could reverse the tumor suppressive effect induced by WTAP silencing. Molecular therapy targeting WTAP-SOD2 may offer novel insights and perspectives for the treatment of CRC.

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WTAP/IGF2BP3介导的m6A修饰SOD2 mRNA可促进结直肠癌的肿瘤发生

Wilms肿瘤1相关蛋白（WTAP）已被证实是多种恶性肿瘤发生和进展的关键调节因子。本研究拟从n6 -甲基腺苷（m6A）修饰的角度探讨WTAP对结直肠癌（CRC）进展的影响。通过qRT-PCR和western blot验证WTAP在临床结直肠癌样本和培养细胞系中的差异表达模式。用菌落形成、transwell和CCK-8进行细胞功能测试。采用MeRIP-qPCR检测wtap介导的CRC细胞中SOD2（超氧化物歧化酶2）mRNA的修饰。采用动物实验对WTAP在体内的功能进行评价。WTAP在结直肠癌样品中随细胞呈高表达模式。WTAP的沉默在体内和体外均能有效抑制结直肠癌的肿瘤发生。机械地，SOD2被确定为WTAP的m6A靶标。wtap介导的m6A修饰SOD2 mRNA以依赖igf2bp3的方式提高其稳定性。同时，SOD2过表达可以逆转WTAP沉默诱导的肿瘤抑制作用。靶向WTAP-SOD2的分子治疗可能为结直肠癌的治疗提供新的见解和视角。

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来源期刊

Journal of Biochemical and Molecular Toxicology 生物-毒理学

CiteScore

5.80

自引率

2.80%

发文量

277

审稿时长

6-12 weeks

期刊介绍： The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.