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N6-methyladenosine-modified HOTAIRM1 promotes vasculogenic mimicry formation in glioma
Cancer Science ( IF 4.5 ) Pub Date : 2022-09-10 , DOI: 10.1111/cas.15578 Zhangyi Wu 1 , Yihai Lin 1 , Nan Wei 2
Cancer Science ( IF 4.5 ) Pub Date : 2022-09-10 , DOI: 10.1111/cas.15578 Zhangyi Wu 1 , Yihai Lin 1 , Nan Wei 2
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Vasculogenic mimicry (VM) has been reported to accelerate angiogenesis in malignant tumors, yet the mechanism underlying VM has not been fully elucidated. N6-methyladenosine (m6A) mainly modulates mRNA fate and affects multiple tumorigenesis. Here, we aimed to investigate m6A-modified HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) in the regulation of glioma-associated VM formation. Gene expression was analyzed by quantitative RT-PCR. Cell viability, metastases, and VM formation capacity were determined by CCK-8, migration and invasion, as well as tube formation assays, respectively. The function and mechanisms of m6A-modified HOTAIRM1 were defined through liquid chromatography–tandem mass spectrometry m6A quantification, methylated RNA immunoprecipitation sequencing, RNA stability assays, and RNA pull-down experiments. A glioma xenograft mouse model was further established for VM evaluation in vivo. The results showed that HOTAIRM1, methyltransferase-like 3 (METTL3), and insulin-like growth factor binding protein 2 (IGFBP2) were upregulated in glioma tissues and cell lines. HOTAIRM1 functions as an oncogene in glioma progression; however, knockdown of HOTAIRM1 significantly reduced cell viability, migration, invasion, and VM formation. Notably, METTL3-dependent m6A modification enhanced HOTAIRM1 mRNA stability, whereas knockdown of METTL3 deficiency significantly suppressed VM in glioma. Moreover, HOTAIRM1 was found to bind IGFBP2, and HOTAIRM1 deficiency blocked glioma progression and VM formation in vivo. Our results indicated that METTL3-dependent m6A-modified HOTAIRM1 promoted VM formation in glioma.
中文翻译：
N6-甲基腺苷修饰的 HOTAIRM1 促进神经胶质瘤中血管生成拟态的形成
据报道，血管生成拟态 (VM) 可加速恶性肿瘤的血管生成，但尚未完全阐明 VM 的潜在机制。N6-甲基腺苷 (m6A) 主要调节 mRNA 命运并影响多种肿瘤发生。在这里，我们旨在研究 m6A 修饰的 HOXA 转录本反义 RNA 骨髓特异性 1 (HOTAIRM1) 在神经胶质瘤相关 VM 形成的调节中的作用。通过定量RT-PCR分析基因表达。细胞活力、转移和 VM 形成能力分别通过 CCK-8、迁移和侵袭以及管形成测定来确定。m6A 修饰的 HOTAIRM1 的功能和机制是通过液相色谱-串联质谱法 m6A 定量、甲基化 RNA 免疫沉淀测序、RNA 稳定性测定和 RNA pull-down 实验确定的。进一步建立神经胶质瘤异种移植小鼠模型用于体内 VM 评估。结果表明，HOTAIRM1、甲基转移酶样 3 (METTL3) 和胰岛素样生长因子结合蛋白 2 (IGFBP2) 在神经胶质瘤组织和细胞系中上调。HOTAIRM1 在神经胶质瘤进展中起致癌基因的作用；然而，HOTAIRM1 的敲低显着降低了细胞活力、迁移、侵袭和 VM 形成。值得注意的是，METTL3 依赖性 m6A 修饰增强了 HOTAIRM1 mRNA 的稳定性，而 METTL3 缺陷的敲低显着抑制了神经胶质瘤中的 VM。此外，发现 HOTAIRM1 与 IGFBP2 结合，并且 HOTAIRM1 缺陷可阻断体内胶质瘤进展和 VM 形成。我们的结果表明，METTL3 依赖性 m6A 修饰的 HOTAIRM1 促进胶质瘤中 VM 的形成。
更新日期：2022-09-10
中文翻译：
N6-甲基腺苷修饰的 HOTAIRM1 促进神经胶质瘤中血管生成拟态的形成
据报道，血管生成拟态 (VM) 可加速恶性肿瘤的血管生成，但尚未完全阐明 VM 的潜在机制。N6-甲基腺苷 (m6A) 主要调节 mRNA 命运并影响多种肿瘤发生。在这里，我们旨在研究 m6A 修饰的 HOXA 转录本反义 RNA 骨髓特异性 1 (HOTAIRM1) 在神经胶质瘤相关 VM 形成的调节中的作用。通过定量RT-PCR分析基因表达。细胞活力、转移和 VM 形成能力分别通过 CCK-8、迁移和侵袭以及管形成测定来确定。m6A 修饰的 HOTAIRM1 的功能和机制是通过液相色谱-串联质谱法 m6A 定量、甲基化 RNA 免疫沉淀测序、RNA 稳定性测定和 RNA pull-down 实验确定的。进一步建立神经胶质瘤异种移植小鼠模型用于体内 VM 评估。结果表明，HOTAIRM1、甲基转移酶样 3 (METTL3) 和胰岛素样生长因子结合蛋白 2 (IGFBP2) 在神经胶质瘤组织和细胞系中上调。HOTAIRM1 在神经胶质瘤进展中起致癌基因的作用；然而，HOTAIRM1 的敲低显着降低了细胞活力、迁移、侵袭和 VM 形成。值得注意的是，METTL3 依赖性 m6A 修饰增强了 HOTAIRM1 mRNA 的稳定性，而 METTL3 缺陷的敲低显着抑制了神经胶质瘤中的 VM。此外，发现 HOTAIRM1 与 IGFBP2 结合，并且 HOTAIRM1 缺陷可阻断体内胶质瘤进展和 VM 形成。我们的结果表明，METTL3 依赖性 m6A 修饰的 HOTAIRM1 促进胶质瘤中 VM 的形成。
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