Department of Neurosurgery, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China.
Department of Oncology, Zhejiang Hospital, No. 12 Lingyin Road, Xihu District, Hangzhou, 310013, Zhejiang, China.
J Transl Med. 2023 Nov 27;21(1):855. doi: 10.1186/s12967-023-04624-3.
HOTAIRM1 is revealed to facilitate the malignant progression of glioma. Vasculogenic mimicry (VM) is critically involved in glioma progression. Nevertheless, the molecular mechanism of HOTAIRM1 in regulating glioma VM formation remains elusive. Thus, we attempted to clarify the role and mechanism of HOTAIRM1 in VM formation in glioma.
qRT-PCR and western blot assays were used to evaluate the gene and protein expression levels of HOTAIRM1 in glioma patient tissue samples and cell lines. The role of HOTAIRM1 in glioma cell progression and VM formation was explored using a series of function gain-and-loss experiments. RNA-binding protein immunoprecipitation (RIP), RNA pull-down, and mechanism experiments were conducted to assess the interaction between HOTAIRM1/METTL3/IGFBP2 axis. Furthermore, rescue assays were conducted to explore the regulatory function of HOTAIRM1/METTL3/IGFBP2 in glioma cell cellular processes and VM formation.
We found that HOTAIRM1 presented up-regulation in glioma tissues and cells and overexpression of HOTAIRM1 facilitated glioma cell proliferation, migration, invasion, and VM formation. Furthermore, overexpression of HOTAIRM1 promoted glioma tumor growth and VM formation capacity in tumor xenograft mouse model. Moreover, HOTAIRM1 was demonstrated to interact with IGFBP2 and positively regulated IGFBP2 expression. IGFBP2 was found to promote glioma cell malignancy and VM formation. Mechanistically, METTL3 was highly expressed in glioma tissues and cells and was bound with HOTAIRM1 which stabilized HOTAIRM1 expression. Rescue assays demonstrated that METTL3 silencing counteracted the impact of HOTAIRM1 on glioma cell malignancy and VM formation capacity.
HOTAIRM1, post-transcriptionally stabilized by METTL3, promotes VM formation in glioma via up-regulating IGFBP2 expression, which provides a new direction for glioma therapy.
HOTAIRM1 被揭示可促进神经胶质瘤的恶性进展。血管生成拟态（VM）在神经胶质瘤的进展中起着至关重要的作用。然而，HOTAIRM1 调节神经胶质瘤 VM 形成的分子机制仍不清楚。因此，我们试图阐明 HOTAIRM1 在神经胶质瘤 VM 形成中的作用和机制。
使用 qRT-PCR 和 Western blot 分析评估 HOTAIRM1 在神经胶质瘤患者组织样本和细胞系中的基因和蛋白表达水平。通过一系列功能获得和丧失实验探讨 HOTAIRM1 在神经胶质瘤细胞进展和 VM 形成中的作用。进行 RNA 结合蛋白免疫沉淀（RIP）、RNA 下拉和机制实验以评估 HOTAIRM1/METTL3/IGFBP2 轴之间的相互作用。此外，进行挽救实验以探讨 HOTAIRM1/METTL3/IGFBP2 在神经胶质瘤细胞生物学过程和 VM 形成中的调节功能。
我们发现 HOTAIRM1 在神经胶质瘤组织和细胞中呈上调表达，过表达 HOTAIRM1 促进神经胶质瘤细胞增殖、迁移、侵袭和 VM 形成。此外，过表达 HOTAIRM1 促进了神经胶质瘤肿瘤异种移植小鼠模型中的肿瘤生长和 VM 形成能力。此外，研究表明 HOTAIRM1 与 IGFBP2 相互作用并正向调节 IGFBP2 的表达。IGFBP2 促进神经胶质瘤细胞恶性肿瘤和 VM 形成。机制上，METTL3 在神经胶质瘤组织和细胞中高表达，并与 HOTAIRM1 结合，稳定 HOTAIRM1 的表达。挽救实验表明，METTL3 沉默可拮抗 HOTAIRM1 对神经胶质瘤细胞恶性肿瘤和 VM 形成能力的影响。
HOTAIRM1 通过 METTL3 转录后稳定，通过上调 IGFBP2 表达促进神经胶质瘤 VM 形成，为神经胶质瘤治疗提供了新的方向。
