Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle-promoting genes.
Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle-promoting genes.
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Roquin1 通过选择性地破坏细胞周期促进基因 mRNA 的稳定性来诱导 G1/S 细胞周期停滞，从而抑制乳腺癌细胞的增殖
DOI：
10.1186/s13046-020-01766-w
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发表时间：
2020-11-23
期刊：
影响因子：
--
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Lu W;Zhou M;Wang B;Liu X;Li B
背景细胞周期进程失调是人类肿瘤细胞的共同特征，但其机制尚不清楚。本研究旨在阐明Roquin 1在乳腺癌细胞周期阻滞中的作用和潜在机制，分析Roquin 1在人类乳腺癌中的表达模式及其与患者生存率的关系。采用实时荧光定量PCR和Western blot检测Roquin 1在乳腺癌组织和细胞系中的表达。采用细胞计数、MTT法、流式细胞术和体内分析等方法研究Roquin 1对细胞增殖、细胞周期进程和肿瘤进展的影响。RNA测序鉴定Roquin 1调控的差异表达基因。采用RNA免疫沉淀法、荧光素酶报告基因法、mRNA半衰期检测法、RNA亲和结合法和RIP-ChIP等方法探讨Roquin 1的分子机制。结果Roquin 1在乳腺癌组织和细胞系中的表达受到抑制，Roquin 1表达降低与乳腺癌患者的总生存率和无复发生存率相关。Roquin 1过表达抑制细胞增殖，诱导G1/S期细胞阻滞，但不引起明显的凋亡。相反，Roquin 1的敲除促进细胞生长和周期进展。此外，Roquin 1的腺病毒体内诱导显着抑制乳腺肿瘤的生长和转移。Roquin 1通过其ROQ结构域靶向mRNA的3′非翻译区（3 'UTR）中的茎环结构，结论Roquin 1是一种新的乳腺癌抑制基因，可诱导G1/G2期细胞凋亡，并可诱导G1/G2期细胞凋亡。通过选择性下调细胞周期促进基因的表达，阻滞S细胞周期，可能成为乳腺癌治疗的潜在分子靶点。
BackgroundDysregulation of cell cycle progression is a common feature of human cancer cells; however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest in breast cancer.MethodsPublic cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and its association with patient survival. Quantitative real-time PCR and Western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assays, flow cytometry, and in vivo analyses were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA sequencing was applied to identify the differentially expressed genes regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1.ResultsWe showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse-free survival of patients with breast cancer. Roquin1 overexpression inhibited cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizes cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2), by targeting the stem–loop structure in the 3′ untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs.ConclusionsOur findings demonstrated that Roquin1 is a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might be a potential molecular target for breast cancer treatment.
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影响因子：
16.6
作者：
Sgromo A;Raisch T;Bawankar P;Bhandari D;Chen Y;Kuzuoğlu-Öztürk D;Weichenrieder O;Izaurralde E
通讯作者：
Izaurralde E
影响因子：
3.7
作者：
Auguste T;Travert M;Tarte K;Amé-Thomas P;Artchounin C;Martin-Garcia N;de Reynies A;de Leval L;Gaulard P;Delfau-Larue MH
通讯作者：
Delfau-Larue MH
影响因子：
16.2
作者：
Feng, Rui-Mei;Zong, Yi-Nan;Xu, Rui-Hua
通讯作者：
Xu, Rui-Hua
影响因子：
11.2
作者：
Lu W;Ning H;Gu L;Peng H;Wang Q;Hou R;Fu M;Hoft DF;Liu J
通讯作者：
Liu J
影响因子：
8
作者：
Khabar, Khalid S. A.
通讯作者：
Khabar, Khalid S. A.