Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China.
Department of Histology and Embryology, School of Basic Medicine, Central South University, Changsha, Hunan, 410013, China.
Cell Death Differ. 2019 Nov;26(11):2329-2343. doi: 10.1038/s41418-019-0304-y. Epub 2019 Feb 20.
The regulatory loop between long noncoding RNAs (lncRNAs) and microRNAs has a dynamic role in transcriptional and translational regulation, and is involved in cancer. However, the regulatory circuitry between lncRNAs and microRNAs in tumorigenesis remains elusive. Here we demonstrate that a nuclear lncRNA LINC00336 is upregulated in lung cancer and functions as an oncogene by acting as a competing endogenous RNA (ceRNAs). LINC00336 bound RNA-binding protein ELAVL1 (ELAV-like RNA-binding protein 1) using nucleotides 1901-2107 of LINC00336 and the RRM interaction domain and key amino acids (aa) of ELAVL1 (aa 101-213), inhibiting ferroptosis. Moreover, ELAVL1 increased LINC00336 expression by stabilizing its posttranscriptional level, whereas LSH (lymphoid-specific helicase) increased ELAVL1 expression through the p53 signaling pathway, further supporting the hypothesis that LSH promotes LINC00336 expression. Interestingly, LINC00336 served as an endogenous sponge of microRNA 6852 (MIR6852) to regulate the expression of cystathionine-β-synthase (CBS), a surrogate marker of ferroptosis. Finally, we found that MIR6852 inhibited cell growth by promoting ferroptosis. These data show that the network of lncRNA and ceRNA has an important role in tumorigenesis and ferroptosis.
长链非编码 RNA（lncRNA）和 microRNA 之间的调控环路在转录和翻译调控中具有动态作用，并参与癌症。然而，lncRNA 和 microRNA 在肿瘤发生中的调控电路仍然难以捉摸。在这里，我们证明核 lncRNA LINC00336 在肺癌中上调，并通过作为竞争性内源 RNA（ceRNA）发挥癌基因作用。LINC00336 通过 LINC00336 的核苷酸 1901-2107 与 RNA 结合蛋白 ELAVL1（ELAV 样 RNA 结合蛋白 1）结合，并与 ELAVL1 的 RRM 相互作用结构域和关键氨基酸（aa）（aa 101-213）结合，抑制铁死亡。此外，ELAVL1 通过稳定其转录后水平增加 LINC00336 的表达，而 LSH（淋巴特异性解旋酶）通过 p53 信号通路增加 ELAVL1 的表达，进一步支持 LSH 促进 LINC00336 表达的假设。有趣的是，LINC00336 作为 microRNA 6852（MIR6852）的内源性海绵，调节胱硫醚-β-合酶（CBS）的表达，CBS 是铁死亡的替代标志物。最后，我们发现 MIR6852 通过促进铁死亡抑制细胞生长。这些数据表明，lncRNA 和 ceRNA 的网络在肿瘤发生和铁死亡中具有重要作用。
