RNA 聚合酶 I (Pol I) 转录的上调和 Pol I 转录机制的过度表达是有利于恶性转化的关键分子改变。然而,这种畸变的致病分子机制在很大程度上仍然未知。在这里,我们发现 Pol I 转录及其核心机制在肺腺癌 (LUAD) 中上调。我们表明,miRNA (miR)-330-5p 和 miR-1270 表达的缺失有助于 LUAD 中 Pol I 转录的上调。这些 miR 在 LUAD 细胞系中的组成型过表达抑制了 Pol I 转录核心成分的表达,并减少了全局核糖体 RNA 合成。重要的是,miR-330-5p/miR-1270 介导的 Pol I 转录抑制发挥了多种肿瘤抑制功能,包括增殖减少、细胞周期停滞、在小鼠异种移植模型中增强细胞凋亡、减少迁移、增加药物敏感性并降低肿瘤负荷。从机制上讲,miR-330-5p 和 miR-1270 的下调分别受 Pol I 亚基衍生的环状 RNA circ_0055467 和 DNA 高甲基化调节。这项研究揭示了一种新的 miR-330-5p/miR-1270 介导的 Pol I 转录的转录后调控,并在 LUAD 中建立了这些 miR 的肿瘤抑制特性。最终,我们的研究结果为 LUAD 的 Pol I 转录机制的治疗靶向提供了理论依据。分别。这项研究揭示了一种新的 miR-330-5p/miR-1270 介导的 Pol I 转录的转录后调控,并在 LUAD 中建立了这些 miR 的肿瘤抑制特性。最终,我们的研究结果为 LUAD 的 Pol I 转录机制的治疗靶向提供了理论依据。分别。这项研究揭示了一种新的 miR-330-5p/miR-1270 介导的 Pol I 转录的转录后调控,并在 LUAD 中建立了这些 miR 的肿瘤抑制特性。最终,我们的研究结果为 LUAD 的 Pol I 转录机制的治疗靶向提供了理论依据。
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MiR-330-5p and miR-1270 target essential components of RNA polymerase I transcription and exhibit a novel tumor suppressor role in lung adenocarcinoma
Upregulation of RNA polymerase I (Pol I) transcription and the overexpression of Pol I transcriptional machinery are crucial molecular alterations favoring malignant transformation. However, the causal molecular mechanism(s) of this aberration remain largely unknown. Here, we found that Pol I transcription and its core machinery are upregulated in lung adenocarcinoma (LUAD). We show that the loss of miRNAs (miR)-330-5p and miR-1270 expression contributes to the upregulation of Pol I transcription in LUAD. Constitutive overexpression of these miRs in LUAD cell lines suppressed the expression of core components of Pol I transcription, and reduced global ribosomal RNA synthesis. Importantly, miR-330-5p/miR-1270-mediated repression of Pol I transcription exerted multiple tumor suppressive functions including reduced proliferation, cell cycle arrest, enhanced apoptosis, reduced migration, increased drug sensitivity, and reduced tumor burden in a mouse xenograft model. Mechanistically, the downregulation of miR-330-5p and miR-1270 is regulated by Pol I subunit-derived circular RNA circ_0055467 and DNA hypermethylation, respectively. This study uncovers a novel miR-330-5p/miR-1270 mediated post-transcriptional regulation of Pol I transcription, and establish tumor suppressor properties of these miRs in LUAD. Ultimately, our findings provide a rationale for the therapeutic targeting of Pol I transcriptional machinery for LUAD.