Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA.
Nucleic Acids Res. 2018 Nov 16;46(20):10635-10648. doi: 10.1093/nar/gky728.
The piwi interacting RNAs (piRNAs) are small non-coding RNAs that specifically bind to the PIWI proteins, a functional requirement. The piRNAs regulate germline development, transposons control, and gene expression. However, piRNA-mediated post-transcriptional gene regulation in human somatic cells is not well understood. We discovered a human piRNA (piR-FTH1) which has a complementary sequence in the ferritin heavy chain 1 (Fth1) mRNA. We demonstrated that expression of piR-FTH1 and Fth1 are inversely correlated in the tested tumor cell lines. We found that piR-FTH1 negatively regulates the Fth1 expression at post-transcriptional level in triple negative breast cancer (TNBC) cells. Additionally, we confirmed that transfected piR-FTH1 knocks down the Fth1 mRNA via the HIWI2 and HILI mediated mechanism. piR-FTH1 mediated Fth1 repression also increased doxorubicin sensitivity by a remarkable 20-fold in TNBC cells. Since the current piRNA-mediated knockdowns of target mRNA are mostly reported in germ line cells, piRNA-mediated post-transcriptional gene regulation in somatic cells is rather unique in its application and mechanistically uses an alternative pathway to siRNA and miRNA. This work begins to lay the groundwork with a broader impact on treatment of various diseases that are linked to elevated levels of specific mRNAs which have a piRNA target.
piRNA 与 PIWI 蛋白特异性结合，这是其发挥功能的必要条件。piRNA 调节生殖细胞发育、转座子控制和基因表达。然而，piRNA 介导的人类体细胞中转录后基因调控机制还不太清楚。我们发现了一种人类 piRNA（piR-FTH1），它在铁蛋白重链 1（Fth1）mRNA 中有一个互补序列。我们证明，在测试的肿瘤细胞系中，piR-FTH1 的表达与 Fth1 的表达呈负相关。我们发现，piR-FTH1 在三阴性乳腺癌（TNBC）细胞中通过 HIWI2 和 HILI 介导的机制在转录后水平负调控 Fth1 的表达。转染的 piR-FTH1 通过 HIWI2 和 HILI 介导的机制敲低 Fth1 mRNA。piR-FTH1 介导的 Fth1 抑制也使 TNBC 细胞对阿霉素的敏感性显著增加了 20 倍。由于目前报道的 piRNA 介导的靶 mRNA 敲低主要发生在生殖细胞中，因此 piRNA 介导的体细胞中转录后基因调控在应用上是独特的，在机制上使用了一种替代 siRNA 和 miRNA 的途径。这项工作为治疗与特定 mRNA 水平升高相关的各种疾病奠定了基础，这些疾病都有 piRNA 靶标。
