Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, P.R. China.
Faculty of Mathematics, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
Mol Ther. 2020 Jun 3;28(6):1479-1493. doi: 10.1016/j.ymthe.2020.03.010. Epub 2020 Mar 19.
The discovery of long noncoding RNAs (lncRNAs) has increased our understanding of the development and progression of many cancers, but their contributions to non-small cell lung cancer (NSCLC) remain poorly understood. Here, we profiled lncRNA expression in NSCLC and investigated in detail the molecular function of one upregulated lncRNA, LINC01234. LINC01234 was overexpressed in NSCLC compared with normal lung tissue and correlated positively with poor prognosis. Downregulation of LINC01234 impaired cell proliferation in vitro and tumor growth in vivo. RNA pull-down/mass spectrometry experiments showed that LINC01234 interacted with the RNA-binding protein heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), which, in turn, led to the recruitment of DiGeorge syndrome critical region gene 8 (DGCR8), a subunit of the microRNA (miRNA) microprocessor complex. Accordingly, depletion of either LINC01234 or HNRNPA2B1 reduced the processing of several miRNA precursors, including primary microRNA (pri-miR)-106b. miR-106b-5p enhanced NSCLC cell growth by downregulating cryptochrome 2 (CRY2), thereby increasing c-Myc expression. Finally, we found that activated c-Myc binds to the LINC01234 promoter to increase its transcription, creating a c-Myc-LINC01234-HNRNPA2B1-miR-106b-5p-CRY2-c-Myc positive-feedback loop. We identified numerous lncRNAs with dysregulated expression in NSCLC and demonstrated a novel oncogenic axis involving LINC01234, HNRNPA2B1, miR-106b-5p, CRY2, and c-Myc. Components of this axis may be potential novel targets for NSCLC.
长链非编码 RNA（lncRNA）的发现增加了我们对许多癌症发生和发展的理解，但它们对非小细胞肺癌（NSCLC）的贡献仍知之甚少。在这里，我们对 NSCLC 中的 lncRNA 表达进行了分析，并详细研究了上调的 lncRNA LINC01234 的分子功能。与正常肺组织相比，LINC01234 在 NSCLC 中过表达，并与不良预后呈正相关。下调 LINC01234 可抑制体外细胞增殖和体内肿瘤生长。RNA 下拉/质谱实验表明，LINC01234 与 RNA 结合蛋白异质核核糖核蛋白 A2/B1（HNRNPA2B1）相互作用，进而导致微小 RNA（miRNA）加工体复合物亚基 DiGeorge 综合征关键区域基因 8（DGCR8）的募集。因此，LINC01234 或 HNRNPA2B1 的耗竭均减少了几种 miRNA 前体的加工，包括初级 miRNA（pri-miR）-106b。miR-106b-5p 通过下调隐花色素 2（CRY2）增强 NSCLC 细胞生长，从而增加 c-Myc 表达。最后，我们发现激活的 c-Myc 结合到 LINC01234 启动子上增加其转录，从而形成 c-Myc-LINC01234-HNRNPA2B1-miR-106b-5p-CRY2-c-Myc 正反馈环。我们鉴定了许多在 NSCLC 中表达失调的 lncRNA，并证实了涉及 LINC01234、HNRNPA2B1、miR-106b-5p、CRY2 和 c-Myc 的新致癌轴。该轴的组成部分可能是 NSCLC 的潜在新靶标。
