LINC00346 promotes pancreatic cancer progression through the CTCF-mediated Myc transcription
LINC00346 promotes pancreatic cancer progression through the CTCF-mediated Myc transcription
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LINC00346 通过 CTCF 介导的 Myc 转录促进胰腺癌进展
DOI：
10.1038/s41388-019-0918-z
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发表时间：
2019-10-10
期刊：
影响因子：
8
通讯作者：
Mo, Yin-Yuan
中科院分区：
文献类型：
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作者：
Peng, Wan-Xin;He, Rong-Zhang;Mo, Yin-Yuan
虽然已知多种因素有助于胰腺导管腺癌（PDAC）进展，但长链非编码RNA（lncRNA）在PDAC中的作用仍然很大程度上未知。在这项研究中，我们提出的数据，长的基因间非编码RNA 346（LINC 00346）的功能作为一个促进因素PDAC的发展。我们首先基于对癌症基因组图谱（TCGA）胰腺癌数据集的询问显示，与正常胰腺组织相比，LINC 00346在胰腺肿瘤标本中高度表达。重要的是，LINC 00346的这种上调分别与总生存期（OS）和无病生存期（DFS）相关。我们进一步表明LINC 00346的敲除（KO）损害胰腺癌细胞增殖、肿瘤发生、迁移和侵袭能力。重要的是，这些表型可以通过KO细胞中LINC 00346的再表达来恢复（即，拯救实验）。RNA沉淀分析结合质谱分析表明，LINC 00346与CCCTC结合因子（CTCF），一个已知的c-Myc的转录抑制因子相互作用。LINC 00346和CTCF之间的这种相互作用阻止CTCF与c-Myc启动子的结合，从而缓解CTCF介导的c-Myc抑制。因此，LINC 00346作为c-Myc的正转录调节因子发挥作用。总之，这些结果表明，LINC 00346通过激活c-Myc促进PDAC发病机制，因此，LINC 00346可以作为PDAC的潜在生物标志物和治疗靶标。
Although multiple factors are known to contribute to pancreatic ductal adenocarcinoma (PDAC) progression, the role of long non-coding RNAs (lncRNAs) in PDAC remains largely unknown. In this study, we present data that long intergenic non-coding RNA 346 (LINC00346) functions as a promoting factor for PDAC development. We first show that LINC00346 is highly expressed in pancreatic tumor specimens as compared to normal pancreatic tissue based on interrogation of The Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma dataset. Of significance, this upregulation of LINC00346 is associated with overall survival (OS) and disease-free survival (DFS), respectively. We further show that knockout (KO) of LINC00346 impairs pancreatic cancer cell proliferation, tumorigenesis, migration, and invasion ability. Importantly, these phenotypes can be restored by LINC00346 re-expression in KO cells (i.e., rescue experiment). RNA precipitation assays combined with mass spectrometry analysis indicate that LINC00346 interacts with CCCTC-binding factor (CTCF), a known transcriptional repressor of c-Myc. This interaction between LINC00346 and CTCF prevents the binding of CTCF to c-Myc promoter, relieving the CTCF-mediated repression of c-Myc. Thus, LINC00346 functions as a positive transcriptional regulator of c-Myc. Together, these results suggest that LINC00346 contributes to PDAC pathogenesis by activating c-Myc, and as such, LINC00346 may serve as a potential biomarker and therapeutic target for PDAC.