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 HM1-3 isoform and that HM1-3 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 HM1-3 isoform in normoxic cells post-transcriptionally induces Hypoxia-Inducible Factor 1α (HIF1α) 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.

中文翻译：

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HOTAIRM1 lncRNA在透明细胞肾细胞癌中被下调并抑制缺氧途径。

HOXA转录反义RNA，髓样特异性1（HOTAIRM1）是一种保守的长非编码RNA（lncRNA），参与髓样和神经分化，在急性髓性白血病和其他癌症中被解除调节。先前的研究集中在核未剪接的HOTAIRM1转录本上，但是存在细胞质剪接变体，其作用仍然未知。在这里，我们报告HOTAIRM1在肾脏中的新功能。HOTAIRM1转录物是在胚胎干细胞的肾谱系分化过程中诱导的，是表达特定肾脏分化基因所必需的。我们显示分化细胞中的主要HOTAIRM1转录物是剪接的胞质HM1-3亚型，并且HM1-3在> 90％的透明细胞肾细胞癌（ccRCCs）中被下调。敲除肾细胞中的HM1-3可以调节缺氧反应性和血管生成基因，包括ANGPTL4。此外，HOTAIRM1转录物被模拟低氧应激下调，敲除常氧细胞中的细胞质HM1-3亚型，转录后诱导缺氧诱导因子1α（HIF1α）蛋白，它是ANGPTL4的关键激活因子。我们的结果证明了ccRCC中特定HOTAIRM1细胞质亚型HM1-3的普遍下调，并暗示了HOTAIRM1在肾脏分化和抑制HIF1依赖性血管生成途径中的可能作用。ANGPTL4的关键激活剂。我们的结果证明了ccRCC中特定HOTAIRM1细胞质亚型HM1-3的普遍下调，并暗示了HOTAIRM1在肾脏分化和抑制HIF1依赖性血管生成途径中的可能作用。ANGPTL4的关键激活剂。我们的结果证明了ccRCC中特定HOTAIRM1细胞质亚型HM1-3的普遍下调，并暗示了HOTAIRM1在肾脏分化和抑制HIF1依赖性血管生成途径中的可能作用。