Department of Neurosurgery, the Second People's Hospital of Yunnan Province, Kunming, China.
Department of Rehabilitation Medicine, The Second People's Hospital of Yunnan Province, Kunming, China.
Pathol Res Pract. 2021 Jul;223:153319. doi: 10.1016/j.prp.2020.153319. Epub 2021 Jan 2.
Nuclear Receptor Subfamily 5 Group A Member 2 (NR5A2, LRH-1) is an oncogene in a wide range of cancer types. Bioinformatics analysis on glioblastoma multiforme (GBM) tumors has revealed that the miR-139-5p-NR5A2 axis may be putatively regulated by the long non-coding RNA (lncRNA) RP3-439F8.1. This led us to hypothesize the existence of a RP3-439F8.1-miR-139-5p-NR5A2 regulatory axis in GBM cells.
Gene expression analysis was performed in GBM tumor samples and normal controls from our hospital, the Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) cohort, and the Gene Expression Omnibus (GEO) database (GSE7696). Cell proliferation, apoptosis, Matrigel Transwell, colony formation, and cell cycle assays were performed in T98 G and U251 cells in vitro. An orthotopic U251 xenograft murine model was employed to test the effects of RP3-439F8.1 knockdown in vivo.
NR5A2 was upregulated in the three independent GBM tumor cohorts. In vitro, NR5A2 overexpression enhanced GBM cell proliferation, colony formation, invasiveness, and G0-G1 cell cycle phase shift via co-activating β-catenin/TCF4 signaling, with no apparent effect upon apoptosis. In contrast, RP3-439F8.1 knockdown produced the opposite effects. RP3-439F8.1 knockdown reduced tumor progression in vivo, increasing overall survival in model mice. Further in vitro experiments revealed that RP3-439F8.1 acts as a competing endogenous RNA (ceRNA) to regulate NR5A2 by sponging the microRNA miR-139-5p. These findings were clinically validated by a positive correlation between RP3-439F8.1 and NR5A2 and a negative correlation between RP3-439F8.1 and miR-139-5p in GBM tumors.
Our study supports a tumorigenic role for RP3-439F8.1 in GBM through the RP3-439F8.1/miR-139-5p/NR5A2 axis.
核受体亚家族 5 组 A 成员 2（NR5A2，LRH-1）是多种癌症类型中的癌基因。对多形性胶质母细胞瘤（GBM）肿瘤的生物信息学分析表明，miR-139-5p-NR5A2 轴可能受长链非编码 RNA（lncRNA）RP3-439F8.1 的推定调节。这使我们假设在 GBM 细胞中存在 RP3-439F8.1-miR-139-5p-NR5A2 调节轴。
在我们医院的 GBM 肿瘤样本和正常对照、癌症基因组图谱胶质母细胞瘤多形性（TCGA-GBM）队列和基因表达综合数据库（GEO）数据库（GSE7696）中进行基因表达分析。在体外的 T98 G 和 U251 细胞中进行细胞增殖、凋亡、Matrigel Transwell、集落形成和细胞周期测定。使用 U251 原位异种移植小鼠模型在体内测试 RP3-439F8.1 敲低的效果。
NR5A2 在三个独立的 GBM 肿瘤队列中上调。在体外，NR5A2 过表达通过共激活 β-连环蛋白/TCF4 信号增强 GBM 细胞增殖、集落形成、侵袭和 G0-G1 细胞周期相移，对细胞凋亡无明显影响。相反，RP3-439F8.1 敲低产生相反的效果。RP3-439F8.1 敲低减少了体内肿瘤的进展，增加了模型小鼠的总生存时间。进一步的体外实验表明，RP3-439F8.1 通过海绵 microRNA miR-139-5p 作为竞争内源性 RNA（ceRNA）来调节 NR5A2。这些发现通过在 GBM 肿瘤中 RP3-439F8.1 与 NR5A2 之间的正相关和 RP3-439F8.1 与 miR-139-5p 之间的负相关得到临床验证。
我们的研究通过 RP3-439F8.1/miR-139-5p/NR5A2 轴支持 RP3-439F8.1 在 GBM 中的致癌作用。
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