KLF5 and MYC modulated LINC00346 contributes to gastric cancer progression through acting as a competing endogeous RNA and indicates poor outcome
KLF5 and MYC modulated LINC00346 contributes to gastric cancer progression through acting as a competing endogeous RNA and indicates poor outcome
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KLF5 和 MYC 调节的 LINC00346 通过充当竞争性内源 RNA 促进胃癌进展，并表明预后不良
DOI：
10.1038/s41418-018-0236-y
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发表时间：
2019-11-01
影响因子：
12.4
通讯作者：
Shu, Yong-qian
中科院分区：
文献类型：
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作者：
Xu, Tong-peng;Ma, Pei;Shu, Yong-qian
本研究基于多个胃癌队列的基因表达综合数据库（GEO），发现长基因间非蛋白编码RNA 346（LINC 00346）是胃癌中异常表达的lncRNA。LINC 00346基因在胃癌中反复扩增和上调，其表达与病理分期差、肿瘤体积大、预后差呈正相关。此外，致癌转录因子KLF 5和MYC可与LINC 00346启动子结合并增强其表达。GEO数据集中的基因集富集分析（GSEA）显示，细胞周期和粘着斑基因在LINC 00346高表达患者中富集。LINC 00346改变的体外和体内测定揭示了影响细胞生长、迁移和侵袭的复杂综合表型。引人注目的是，LINC 00346改变后的高通量测序分析突出显示了GC细胞中细胞周期和粘着斑途径的改变。从机制上讲，Argonaute 2（Ago 2）被LINC 00346募集，LINC 00346通过拮抗miR-34 a-5 p抑制CD 44、NOTCH 1和AXL蛋白翻译的能力，充当miR-34 a-5 p的分子海绵。综上所述，我们的研究结果支持了一个模型，其中KLF 5，MYC/LINC 00346/miR-34 a-5 p串扰在GC肿瘤发生和进展中起关键作用，这表明了治疗GC的新治疗方向。
It was found in this study that long intergenic non-protein coding RNA 346 (LINC00346) was an lncRNA aberrantly expressed in gastric cancer (GC) based on multiple Gene Expression Omnibus (GEO) databases of GC cohorts. The LINC00346 gene was recurrently amplified and upregulated in GC, and its expression was positively correlated with poor pathologic stage, large tumor size, and poor prognosis. In addition, the oncogenic transcription factors KLF5 and MYC could bind to the LINC00346 promoter and enhance its expression. Gene Set Enrichment Analysis (GSEA) in the GEO datasets revealed that cell cycle and focal adhesion genes were enriched in patients with high LINC00346 expression. In vitro and in vivo assays of LINC00346 alterations revealed a complex integrated phenotype affecting cell growth, migration and invasion. Strikingly, high-throughput sequencing analysis after LINC00346 alterations highlighted alterations in cell cycle and focal adhesion pathways in GC cells. Mechanistically, argonaute 2 (Ago2) was recruited by LINC00346, which functioned as a molecular sponge for miR-34a-5p by antagonizing its ability to repress CD44, NOTCH1, and AXL protein translation. Taken together, our findings support a model in which the KLF5, MYC/LINC00346/miR-34a-5p cross-talk served as critical effectors in GC tumorigenesis and progression, suggesting a new therapeutic direction in the treatment of GC.