IGF2BP2 inhibits invasion and migration of clear cell renal cell carcinoma via targeting Netrin-4 in an m6A-dependent manner.

IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Carcinogenesis Pub Date : 2024-08-01 Epub Date: 2024-05-23 DOI:10.1002/mc.23746
Gui Wang, Tao Zhuang, Fei Zhen, Chu Zhang, Qichao Wang, Xu Miao, Nienie Qi, Ruiqin Yao
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Abstract

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, often leads to a poor prognosis due to metastasis. The investigation of N6-methyladenosine (m6A) methylation, a crucial RNA modification, and its role in ccRCC, particularly through the m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), revealed significant insights. We found that IGF2BP2 was notably downregulated in ccRCC, which correlated with tumor aggressiveness and poor prognosis. Thus, IGFBP2 has emerged as an independent prognostic factor of ccRCC. Moreover, a strong positive correlation was observed between the expression of IGF2BP2 and Netrin-4. Netrin-4 was also downregulated in ccRCC, and its lower levels were associated with increased malignancy and poor prognosis. Overexpression of IGF2BP2 and Netrin-4 suppressed the invasion and migration of ccRCC cells, while Netrin-4 knockdown reversed these effects in ccRCC cell lines. RNA immunoprecipitation (RIP)-quantitative polymerase chain reaction validated the robust enrichment of Netrin-4 mRNA in anti-IGF2BP2 antibody immunoprecipitates. MeRlP showed significantly increased Netrin4 m6A levels after lGF2BP2 overexpression. Moreover, we found that IGF2BP2 recognized and bound to the m6A site within the coding sequence of Netrin-4, enhancing its mRNA stability. Collectively, these results showed that IGF2BP2 plays a suppressive role in the invasion and migration of ccRCC cells by targeting Netrin-4 in an m6A-dependent manner. These findings underscore the potential of IGF2BP2/Netrin-4 as a promising prognostic biomarker and therapeutic target in patients with ccRCC metastasis.

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IGF2BP2 以 m6A 依赖性方式通过靶向 Netrin-4 抑制透明细胞肾细胞癌的侵袭和迁移。
透明细胞肾细胞癌(ccRCC)是肾细胞癌中最常见的亚型,往往因转移而导致预后不良。N6-甲基腺苷(m6A)甲基化是一种关键的RNA修饰,研究它在ccRCC中的作用,特别是通过m6A读取胰岛素样生长因子2 mRNA结合蛋白2(IGF2BP2)的甲基化,揭示了重要的见解。我们发现,IGF2BP2 在 ccRCC 中明显下调,这与肿瘤的侵袭性和预后不良有关。因此,IGFBP2 已成为 ccRCC 的一个独立预后因素。此外,还观察到 IGF2BP2 的表达与 Netrin-4 之间存在很强的正相关性。Netrin-4也在ccRCC中下调,其水平较低与恶性程度增加和预后不良有关。在ccRCC细胞系中,过表达IGF2BP2和Netrin-4可抑制ccRCC细胞的侵袭和迁移,而Netrin-4的敲除可逆转这些效应。RNA免疫沉淀(RIP)-定量聚合酶链反应验证了抗IGF2BP2抗体免疫沉淀物中Netrin-4 mRNA的强力富集。MeRlP显示,lGF2BP2过表达后,Netrin4 m6A水平明显增加。此外,我们还发现 IGF2BP2 能识别并结合 Netrin-4 编码序列中的 m6A 位点,从而增强其 mRNA 的稳定性。总之,这些结果表明,IGF2BP2 通过以 m6A 依赖性方式靶向 Netrin-4 在 ccRCC 细胞的侵袭和迁移中起抑制作用。这些发现强调了IGF2BP2/Netrin-4作为ccRCC转移患者预后生物标志物和治疗靶点的潜力。
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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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