Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University Cancer Center, Lund, Sweden.
BioCARE, Strategic Cancer Research Program, Lund, Sweden.
Sci Rep. 2016 Oct 18;6:35664. doi: 10.1038/srep35664.
We previously reported that the human HER2 gene encodes the intronic microRNA mir-4728, which is overexpressed together with its oncogenic host gene and may act independently of the HER2 receptor. More recently, we also reported that the oncogenic miR-21-5p is regulated by 3' tailing and trimming by the non-canonical poly(A) polymerase PAPD5 and the ribonuclease PARN. Here we demonstrate a dual function for the HER2 locus in upregulation of miR-21-5p; while HER2 signalling activates transcription of mir-21, miR-4728-3p specifically stabilises miR-21-5p through inhibition of PAPD5. Our results establish a new and unexpected oncogenic role for the HER2 locus that is not currently being targeted by any anti-HER2 therapy.
我们之前曾报道，人类 HER2 基因编码内含子 microRNA mir-4728，其与致癌宿主基因一起过表达，并且可能独立于 HER2 受体发挥作用。最近，我们还报道了致癌 miR-21-5p 受到非典型 poly(A)聚合酶 PAPD5 和核糖核酸酶 PARN 的 3'尾端和修剪的调控。在这里，我们证明了 HER2 基因座在 miR-21-5p 的上调中具有双重功能；虽然 HER2 信号激活 mir-21 的转录，但 miR-4728-3p 通过抑制 PAPD5 特异性稳定 miR-21-5p。我们的结果确立了 HER2 基因座的一个新的、意想不到的致癌作用，目前任何抗 HER2 治疗都没有针对这一作用。
