N6-甲基腺苷 (m6A) 是真核 mRNA 中丰富的可逆修饰。新的证据表明 m6A 修饰在肿瘤发生中起着至关重要的作用。作为 m6A 的关键读者，IGF2BP3 通常通过 m6A 依赖性方式介导 mRNA 的稳定。但IGF2BP3在三阴性乳腺癌(TNBC)肿瘤发生中的潜在机制尚不清楚。TCGA队列分析了不同乳腺癌亚型中IGF2BP3的表达和IGF2BP3启动子甲基化水平。进行集落形成、流式细胞术测定和皮下异种移植来鉴定 TNBC 中 IGF2BP3 的表型。采用RNA/RNA免疫沉淀(RIP)/甲基化RNA免疫沉淀(MeRIP)测序和荧光素酶测定来验证TNBC细胞中IGF2BP3的靶标。IGF2BP3在TNBC细胞系和组织中高表达。 TET3介导的IGF2BP3启动子低甲基化导致IGF2BP3上调。敲低IGF2BP3可显着降低体外和体内TNBC的增殖。交叉联合测定显示 IGF2BP3 通过 m6A 依赖性方式降低神经纤维蛋白 1 (NF1) 的稳定性。 NF1敲低可以部分挽救IGF2BP3敲低细胞的表型。TET3介导的IGF2BP3通过m6A依赖性方式破坏NF1 mRNA的稳定性，加速TNBC的增殖。这表明 IGF2BP3 可能成为 TNBC 的潜在治疗靶点。© 2023 作者。约翰·威利出版的《临床与转化医学》

N6-methyladenosine (m6A) is an abundant reversible modification in eukaryotic mRNAs. Emerging evidences indicate that m6A modification plays a vital role in tumourigenesis. As a crucial reader of m6A, IGF2BP3 usually mediates the stabilisation of mRNAs via an m6A-dependent manner. But the underlying mechanism of IGF2BP3 in the tumourigenesis of triple-negative breast cancer (TNBC) is unclear.TCGA cohorts were analysed for IGF2BP3 expression and IGF2BP3 promoter methylation levels in different breast cancer subtypes. Colony formation, flow cytometry assays and subcutaneous xenograft were performed to identify the phenotype of IGF2BP3 in TNBC. RNA/RNA immunoprecipitation (RIP)/methylated RNA immunoprecipitation (MeRIP) sequencing and luciferase assays were used to certify the target of IGF2BP3 in TNBC cells.IGF2BP3 was highly expressed in TNBC cell lines and tissues. TET3-mediated IGF2BP3 promoter hypomethylation led to the upregulation of IGF2BP3. Knocking down IGF2BP3 markedly reduced the proliferation of TNBC in vitro and in vivo. Intersection co-assays revealed that IGF2BP3 decreased neurofibromin 1 (NF1) stabilisation via an m6A-dependent manner. NF1 knockdown could rescue the phenotypes of IGF2BP3 knockdown cells partially.TET3-mediated IGF2BP3 accelerated the proliferation of TNBC by destabilising NF1 mRNA via an m6A-dependent manner. This suggests that IGF2BP3 could be a potential therapeutic target for TNBC.© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.