PTBP3 splicing factor promotes hepatocellular carcinoma by destroying the splicing balance of NEAT1 and pre-miR-612 (Retracted article. See MAR, 2023)
PTBP3 splicing factor promotes hepatocellular carcinoma by destroying the splicing balance of NEAT1 and pre-miR-612 (Retracted article. See MAR, 2023)
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PTBP3剪接因子通过破坏NEAT1和pre-miR-612的剪接平衡促进肝细胞癌发生
DOI：
10.1038/s41388-018-0416-8
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发表时间：
2018-12-13
期刊：
影响因子：
8
通讯作者：
Dou, Kefeng
中科院分区：
文献类型：
--
作者：
Yang, Xisheng;Qu, Shibin;Dou, Kefeng
核富集RNA结合蛋白（RBP）主要参与转录调控，是调节基因多样性和表达水平的关键检查点。我们分析了人HCC组织和匹配的正常对照组织中的核RBP。基于基因表达水平，PTBP 3被鉴定为在HCC细胞核中排名靠前。然后用siRNA或慢病毒载体转染HCC细胞系。PTBP 3在体内外均能促进肝癌细胞增殖和转移。RNA免疫沉淀（RIP）、荧光原位杂交（FISH）和qRT-PCR分析证实PTBP 3蛋白在细胞核中募集丰富的lnc-NEAT 1剪接变体（NEAT 1_1和NEAT 1_2）和pre-miR-612（miR-612的前体）。通过PTBP 3测定NEAT1_1、NEAT1_2和miR-612表达水平。相关性分析显示PTBP 3与NEAT 1呈正相关，而与miR-612呈负相关。NEAT 1和miR-612分别检测HCC中P53/CCND 1和AKT 2/EMT通路。PTBP 3（高）和NEAT 1（高）/miR-612（低）患者的总生存期较短。因此，核富集的RBP，PTBP 3，通过调节HCC中剪接变体（NEAT1_1，NEAT1_2和miR-612）的平衡促进HCC细胞恶性生长和转移。
Nuclear-enriched RNA-binding proteins (RBPs) are mainly involved in transcriptional regulation, which is a critical checkpoint to tune gene diversity and expression levels. We analyzed nuclear RBPs in human HCC tissues and matched normal control tissues. Based on the gene expression levels, PTBP3 was identified as top-ranked in the nuclei of HCC cells. HCC cell lines then were transfected with siRNAs or lentiviral vectors. PTBP3 promoted HCC cell proliferation and metastasis both in vitro and in vivo. RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH) and qRT-PCR assays verified that PTBP3 protein recruited abundant lnc-NEAT1 splicing variants (NEAT1_1 and NEAT1_2) and pre-miR-612 (precursor of miR-612) in the nucleus. NEAT1_1, NEAT1_2 and miR-612 expression levels were determined by PTBP3. Correlational analyses revealed that PTBP3 was positively correlated with NEAT1, but it was inversely correlated with miR-612 in HCC. The P53/CCND1 and AKT2/EMT pathways were determined by NEAT1 and miR-612 respectively in HCC. The PTBP3(high) and NEAT1(high)/miR-612(low) patients had a shorter overall survival. Therefore, nuclear-enriched RBP, PTBP3, promotes HCC cell malignant growth and metastasis by regulating the balance of splicing variants (NEAT1_1, NEAT1_2 and miR-612) in HCC.