Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, B.C, V5Z 1L3, Canada.
Sci Rep. 2018 Jan 9;8(1):152. doi: 10.1038/s41598-017-18462-z.
Hypoxia promotes tumour aggressiveness and reduces patient survival. A spectrum of poor outcome among patients with hypoxic tumours suggests that additional factors modulate how tumours respond to hypoxia. PIWI-interacting RNAs (piRNAs) are small non-coding RNAs with a pivotal role in genomic stability and epigenetic regulation of gene expression. We reported that cancer type-specific piRNA signatures vary among patients. However, remarkably homogenous piRNA profiles are detected across patients with renal cell carcinoma, a cancer characterized by constitutive upregulation of hypoxia-related signaling induced by common mutation or loss of von Hippel-Lindau factor (VHL). By investigating >3000 piRNA transcriptomes in hypoxic and non-hypoxic tumors from seven organs, we discovered 40 hypoxia-regulated piRNAs and validated this in cells cultured under hypoxia. Moreover, a subset of these hypoxia-regulated piRNAs are regulated by VHL/HIF signaling in vitro. A hypoxia-regulated piRNA-based score (PiSco) was associated with poor RFS for hypoxic tumours, particularly Stage I lung adenocarcinomas, suggesting that hypoxia-regulated piRNA expression can predict tumour recurrence even in early-stage tumours and thus may be of clinical utility.
缺氧促进肿瘤侵袭性并降低患者生存率。缺氧肿瘤患者的一系列不良预后表明，还有其他因素调节肿瘤对缺氧的反应。PIWI 相互作用 RNA（piRNA）是一类小的非编码 RNA，在基因组稳定性和基因表达的表观遗传调控中具有关键作用。我们报道了癌症类型特异性 piRNA 特征在患者之间存在差异。然而，在肾细胞癌患者中检测到的 piRNA 图谱非常相似，肾细胞癌是一种由常见突变或 von Hippel-Lindau 因子（VHL）缺失导致的缺氧相关信号持续上调的癌症。通过对来自七个器官的缺氧和非缺氧肿瘤中的超过 3000 个 piRNA 转录组进行研究，我们发现了 40 个受缺氧调节的 piRNA，并在缺氧培养的细胞中对此进行了验证。此外，这些受缺氧调节的 piRNA 中的一部分受 VHL/HIF 信号通路在体外调节。基于缺氧调节 piRNA 的评分（PiSco）与缺氧肿瘤的不良 RFS 相关，特别是 I 期肺腺癌，这表明缺氧调节 piRNA 的表达甚至可以预测早期肿瘤的肿瘤复发，因此可能具有临床应用价值。
