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病理阶段相关非编码 RNA 长基因间非蛋白编码 RNA 1234(LINC01234)通过海绵 microRNA(miR)-140-3p 介导的含溴结构域蛋白 4(BRD4)表达调节参与肾上腺皮质癌细胞周期调控。

Pathological stage-associated non-coding RNA long intergenic non-protein coding RNA 1234 (LINC01234) participation in cell cycle regulation in adrenocortical carcinoma through bromodomain-containing protein 4 (BRD4) expression mediation via sponging microRNA (miR)-140-3p.

机构信息

Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Huangpu, Shanghai, China.

出版信息

Bioengineered. 2022 May;13(5):13607-13621. doi: 10.1080/21655979.2022.2081464.

Abstract

Many researches indicated that long non-coding RNAs (lncRNAs) were involved in the malignant progression of tumors, including Adrenocortical Carcinoma (ACC). However, as for most lncRNAs, their biological behaviors and molecular mechanism remain unclear in ACC. In the present research, weighted gene co-expression network analysis (WGCNA) was used to identify pathologically relevant gene, including lncRNAs. By comparing their expressions in GSE61359 tumors and normal controls, long intergenic non-protein coding RNA 1234 (LINC01234) was selected to investigate the clinical significance, biological function, and mechanism in ACC. Data mining revealed that LINC01234 expression was significantly up-regulated in ACC patients, and a shorter survival time presents in patients with higher LINC01234 expression compared to that in patients with lower LINC01234 expression. Further, LINC01234 silencing resulted in cells growth arrest in vitro and in vivo. Mechanism studies suggested that LINC01234 silencing induced cell cycle arrest, and bromodomain-containing protein 4 (BRD4) overexpression could restore this phenomenon. Further research showed that LINC01234 could mediate BRD4 expression through competitively sequestering microRNA (miR)-140-3p, as evidenced by the positive correlation of LINC01234 with BRD4 and inverse correlation with miR-140-3p expression. Luciferase activity assay also verified the targeting relationship between LINC01234, BRD4 and miR-140-3p. And up-regulated LINC01234 in ACC cells significantly reversed the degradation of BRD4 by miR-140-3p. Collectively, we deduce that LINC01234 functions as a ceRNA to regulate BRD4 expression by sponging miR-140-3p in ACC progress. Our findings have the potential to provide a new target for the diagnosis and treatment of ACC.

摘要

许多研究表明,长链非编码 RNA(lncRNAs)参与了肿瘤的恶性进展,包括肾上腺皮质癌(ACC)。然而,对于大多数 lncRNAs 而言,其在 ACC 中的生物学行为和分子机制仍不清楚。在本研究中,使用加权基因共表达网络分析(WGCNA)来鉴定与病理相关的基因,包括 lncRNAs。通过比较 GSE61359 肿瘤和正常对照中的表达,选择长链非编码 RNA 1234(LINC01234)来研究其在 ACC 中的临床意义、生物学功能和机制。数据挖掘显示,LINC01234 在 ACC 患者中表达显著上调,且表达较高的患者的生存时间明显短于表达较低的患者。进一步的,LINC01234 的沉默导致细胞在体外和体内生长停滞。机制研究表明,LINC01234 的沉默诱导细胞周期停滞,而溴结构域蛋白 4(BRD4)的过表达可以恢复这种现象。进一步的研究表明,LINC01234 通过竞争性地结合 microRNA(miR)-140-3p 来介导 BRD4 的表达,这一点可以通过 LINC01234 与 BRD4 的正相关和与 miR-140-3p 的负相关来证明。荧光素酶活性测定也验证了 LINC01234、BRD4 和 miR-140-3p 之间的靶向关系。并且在 ACC 细胞中上调的 LINC01234 显著逆转了 miR-140-3p 对 BRD4 的降解。综上所述,我们推断 LINC01234 通过海绵吸附 miR-140-3p 作为 ceRNA 来调节 BRD4 在 ACC 进展中的表达。我们的研究结果有可能为 ACC 的诊断和治疗提供新的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/636d/9275903/8c098fe9d35e/KBIE_A_2081464_UF0001_OC.jpg

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