Long Noncoding RNA MPRL Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via Disruption of Pre-miRNA Processing.
Long Noncoding RNA MPRL Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via Disruption of Pre-miRNA Processing.
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长非编码 RNA MPRL 通过破坏 Pre-miRNA 加工促进线粒体裂变和顺铂化学敏感性
DOI：
10.1158/1078-0432.ccr-18-2739
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发表时间：
2019-06-15
期刊：
影响因子：
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通讯作者：
Fan S
中科院分区：
文献类型：
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作者：
Tian T;Lv X;Pan G;Lu Y;Chen W;He W;Lei X;Zhang H;Liu M;Sun S;Ou Z;Lin X;Cai L;He L;Tu Z;Wang X;Tannous BA;Ferrone S;Li J;Fan S
大部分长链非编码RNA（lncRNA）在化疗敏感性中的整体生物学作用和临床意义尚未完全了解。我们研究了舌鳞状细胞癌（tongue squamous cell carcinoma，TSCC）中lncRNA NR_034085（miRNA processing related lncRNA，MPRL）的生物学功能、作用机制及其临床意义。通过lncRNA微阵列测量顺铂处理的TSCC细胞系中的lncRNA表达，并在TSCC组织中证实。一系列的体外和体内实验证实了MPRL的功能作用。采用miRNA谱、RNA pull-down、RNA免疫沉淀、序列缺失分析和荧光素酶分析等方法研究MPRL的可能机制。我们发现，MPRL的表达显着上调TSCC细胞系与顺铂和E2 F1的反式激活。MPRL通过miR-483- 5 p控制线粒体分裂和顺铂敏感性。在探索MPRL和miR-483- 5 p之间的潜在相互作用时，我们确定了细胞质MPRL直接结合环区域内的pre-miR-483，并阻断pre-miR-483被TRBP-DICER-复合物识别和切割，从而抑制miR-483 - 5 p的产生并上调miR-483- 5 p下游target-FIS 1表达。此外，过表达或敲低MPRL改变了小鼠异种移植物中的肿瘤凋亡和生长。重要的是，我们发现MPRL和pre-miR-483的高表达以及miR-483- 5 p的低表达与新辅助化疗敏感性和更好的TSCC患者预后显著相关。我们提出了一个模型，其中lncRNA损害微处理器识别和pre-miRNA-cropping的效率。此外，我们的研究揭示了一种新的线粒体分裂和化疗敏感性的调控网络，以及预测TSCC新辅助化疗敏感性的新生物标志物。
The overall biological roles and clinical significance of most long noncoding RNAs(lncRNAs) in chemosensitivity are not fully understood. We investigated the biological function, mechanism and clinical significance of lncRNA NR_034085, which we termed miRNA processing related lncRNA(MPRL), in tongue squamous cell carcinoma(TSCC). LncRNA expression in TSCC cell lines with cisplatin treatment was measured by lncRNA microarray and confirmed in TSCC tissues. The functional roles of MPRL were demonstrated by a series of in-vitro and in-vivo experiments. The miRNA profiles, RNA pull-down, RNA immunoprecipitation, serial deletion analysis and luciferase analyses were used to investigate the potential mechanisms of MPRL. We found that MPRL expression was significantly upregulated in TSCC cell lines treated with cisplatin and transactivated by E2F1. MPRL controlled mitochondrial fission and cisplatin sensitivity through miR-483–5p. In exploring the underlying interaction between MPRL and miR-483–5p, we identified that cytoplasmic MPRL directly binds to pre-miR-483 within the loop region and blocks pre-miR-483 recognition and cleavage by TRBP-DICER-complex, thereby inhibiting miR-483–5p generation and upregulating miR-483–5p downstream target-FIS1 expression. Furthermore, overexpression or knockdown MPRL altered tumor apoptosis and growth in mouse xenografts. Importantly, we found that high expression of MPRL and pre-miR-483, and low expression of miR-483–5p were significantly associated with neoadjuvant chemosensitivity and better TSCC patients’ prognosis. We propose a model in which lncRNAs impair microprocessor recognition and efficient of pre-miRNA-cropping. In addition, our study reveals a novel regulatory network for mitochondrial fission and chemosensitivity and new biomarkers for predication of neoadjuvant chemosensitivity in TSCC.