HOTAIRM1 lncRNA is downregulated in clear cell renal cell carcinoma and inhibits the hypoxia pathway
HOTAIRM1 lncRNA is downregulated in clear cell renal cell carcinoma and inhibits the hypoxia pathway
复制标题
HOTAIRM1 lncRNA在肾透明细胞癌中下调并抑制缺氧通路
DOI：
10.1016/j.canlet.2019.12.022
复制
发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Martinez, Ernest
中科院分区：
文献类型：
--
作者：
Hamilton, Michael J.;Young, Matthew;Martinez, Ernest
HOXA转录反义RNA，骨髓特异性1（HOTAIRM 1）是一种保守的长链非编码RNA（lncRNA），参与骨髓和神经分化，在急性髓性白血病和其他癌症中失调。以前的研究主要集中在核未剪接HOTAIRM 1转录本，但存在细胞质剪接变体，其作用仍然未知。在这里，我们报告了HOTAIRM 1在肾脏中的新功能。HOTAIRM 1转录物在胚胎干细胞的肾谱系分化过程中被诱导，并且是特异性肾分化基因表达所需的。我们表明，分化细胞中的主要HOTAIRM 1转录物是剪接的细胞质HMI-3同种型，并且HMI-3在> 90%的透明细胞肾细胞癌（ccRCC）中下调。肾细胞中HM 1 -3的敲低使低氧反应和血管生成基因（包括ANGPTL 4）失调。此外，HOTAIRM 1转录物被低氧模拟应激下调，并且在转录后诱导低氧诱导因子1 α（HIF 1 α）蛋白（ANGPTL 4的关键激活因子）的常氧细胞中敲低细胞质HMI-3亚型。我们的结果表明，ccRCC中特异性HOTAIRM 1细胞质亚型HM 1 -3的普遍下调，并表明HOTAIRM 1在肾脏分化和抑制HIF 1依赖性血管生成途径中可能发挥作用。
HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) is a conserved long non-coding RNA (lncRNA) involved in myeloid and neural differentiation that is deregulated in acute myeloid leukemia and other cancers. Previous studies focused on the nuclear unspliced HOTAIRM1 transcript, however cytoplasmic splice variants exist whose roles have remained unknown. Here, we report novel functions of HOTAIRM1 in the kidney. HOTAIRM1 transcripts are induced during renal lineage differentiation of embryonic stem cells and required for expression of specific renal differentiation genes. We show that the major HOTAIRM1 transcript in differentiated cells is the spliced cytoplasmic HMI-3 isoform and that HMI-3 is downregulated in > 90% of clear cell renal cell carcinomas (ccRCCs). Knockdown of HM1-3 in renal cells deregulates hypoxia-responsive and angiogenic genes, including ANGPTL4. Furthermore, HOTAIRM1 transcripts are downregulated by hypoxia-mimetic stress and knockdown of the cytoplasmic HMI-3 isoform in normoxic cells post-transcriptionally induces Hypoxia-Inducible Factor 1 alpha (HIF1 alpha) protein, a key activator of ANGPTL4. Our results demonstrate the pervasive downregulation of the specific HOTAIRM1 cytoplasmic isoform HM1-3 in ccRCC and suggest possible roles of HOTAIRM1 in kidney differentiation and suppression of HIF1-dependent angiogenic pathways.