LncRNA SNORD3A specifically sensitizes breast cancer cells to 5-FU by sponging miR-185-5p to enhance UMPS expression
LncRNA SNORD3A specifically sensitizes breast cancer cells to 5-FU by sponging miR-185-5p to enhance UMPS expression
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LncRNA SNORD3A 通过海绵 miR-185-5p 来增强 UMPS 表达，从而特异性地使乳腺癌细胞对 5-FU 敏感
DOI：
10.1038/s41419-020-2557-2
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发表时间：
2020-05-07
影响因子：
9
通讯作者：
Zheng, Guopei
中科院分区：
文献类型：
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作者：
Luo, Liyun;Zhang, Jianlei;Zheng, Guopei
乳腺癌是女性最常见的癌症类型。长非编码RNA(LncRNAs)已被报道为潜在的新的癌症诊断标记物、预后因素和治疗靶点。然而，lncRNAs在乳腺癌中的具体作用和机制仍有待阐明。在这里，我们证明了lncRNA SNORD3A在乳腺癌细胞和组织中的下调，并验证了它的非蛋白质编码特性。SNORD3A过表达对细胞增殖无影响，但在体内外对5-氟尿嘧啶(5-FU)具有特异性增敏作用。机制上，SNORD3A通过促进尿苷一磷酸合成酶(UMPS)蛋白表达发挥作用。SNORD3A作为miR-185-5P的竞争内源RNA，导致UMPS蛋白上调。在体内外，miR-185-5p过表达阻断了SNORD3A对5-FU的化疗增敏作用。此外，Meis1过表达在转录上促进SNORD3A的表达，而Meis1在乳腺癌细胞和组织中下调表达。在乳腺癌组织中，SNORD3A水平与Meis1、UMPS蛋白水平呈正相关，而miR-185-5p水平与UMPS蛋白水平呈负相关。在接受5-FU化疗的乳腺癌患者中，高水平的SNORD3A转录本和Meis1和UMPS蛋白水平预示着较好的预后，但高miR-185-5p水平预示着较差的预后。我们的发现表明，Meis1调控的SNORD3A通过增强UMPS的表达而特异性地增敏乳腺癌细胞对5-FU的敏感性。SNORD3A-UMPS轴可能成为提高5-FU为主的乳腺癌化疗疗效的潜在生物标志物和治疗靶点。
Breast cancer is the most common cancer type in women. Long non-coding RNAs (lncRNAs) have been reported as potential new diagnostic markers, prognostic factors, and therapeutic targets in cancer. However, the specific roles and mechanisms of lncRNAs in breast cancer remain to be elucidated. Here we demonstrated the downregulation of lncRNA SNORD3A in breast cancer cells and tissues and verified its non-protein-coding property. SNORD3A overexpression had no effect on cell proliferation but specifically sensitized breast cancer cells to 5-fluorouracil (5-FU) in vitro and in vivo. Mechanistically, SNORD3A exerts its effect via enhancing uridine monophosphate synthetase (UMPS) protein expression. SNORD3A acts as a competing endogenous RNA for miR-185-5p, leading to UMPS protein upregulation. miR-185-5p overexpression disrupted the effect of SNORD3A on chemosensitization to 5-FU in vitro and in vivo. Moreover, Meis1 overexpression transcriptionally promotes SNORD3A expression, and Meis1 is downregulated in breast cancer cells and tissues. In breast cancer tissues, SNORD3A level positively correlates with Meis1 and UMPS protein levels, whereas miR-185-5p level negatively correlates with UMPS protein level. High SNORD3A transcript and Meis1 and UMPS protein levels predicts a better outcome, but high miR-185-5p level predicts a worse outcome in breast cancer patients receiving 5-FU-based chemotherapy. Our findings indicate that Meis1-regulated SNORD3A specifically sensitizes breast cancer cells to 5-FU via enhancing UMPS expression. The SNORD3A–UMPS axis may serve as a potential biomarker and therapeutic target to improve the efficacy of 5-FU-based chemotherapy for breast cancer patients.