Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and University of Western Australia Centre for Medical Research, Royal Perth Hospital, Perth, Western Australia 6000, Australia.
Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and University of Western Australia Centre for Medical Research, Royal Perth Hospital, Perth, Western Australia 6000, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia 6008, Australia.
J Biol Chem. 2011 Dec 2;286(48):41442-41454. doi: 10.1074/jbc.M111.301481. Epub 2011 Oct 4.
ERBB-2 overexpression is associated with the development and progression of cancer and mediates its resistance to therapy. It has been suggested that post-transcriptional mechanisms control the overexpression of ERBB-2 in prostate cancer (PCa). We recently demonstrated that the 3'-untranslated region (3'-UTR) of ERBB-2 mRNA contains two specific target sites for binding of the microRNA miR-331-3p and that miR-331-3p represses ERBB-2 expression and signaling in PCa cells. Here we investigate a U-rich element situated in close proximity to the distal miR-331-3p target site in the ERBB-2 3'-UTR. Specific binding of HuR to this U-rich element promotes ERBB-2 expression in PCa cells. We show that HuR antagonizes the repressive action of miR-331-3p on its distal ERBB-2 3'-UTR target site. These results support a model in which the interplay between RNA-binding proteins and microRNAs controls the post-transcriptional regulation of gene expression and suggest that both HuR and miR-331-3p participate in the overexpression of ERBB-2 observed in some PCas.
erbB-2 过表达与癌症的发生和发展有关，并介导其对治疗的耐药性。已经有人提出，转录后机制控制着前列腺癌（PCa）中 erbB-2 的过表达。我们最近证明，erbB-2 mRNA 的 3'-非翻译区（3'-UTR）包含两个特定的结合位点，供 microRNA miR-331-3p 结合，并且 miR-331-3p 在 PCa 细胞中抑制 erbB-2 的表达和信号传导。在这里，我们研究了位于 erbB-2 3'-UTR 中远端 miR-331-3p 靶位点附近的富含 U 的元件。HuR 特异性结合该 U 富含元件可促进 PCa 细胞中 erbB-2 的表达。我们表明 HuR 拮抗 miR-331-3p 对其远端 erbB-2 3'-UTR 靶位点的抑制作用。这些结果支持了一种模型，即 RNA 结合蛋白和 microRNAs 之间的相互作用控制基因表达的转录后调控，并表明 HuR 和 miR-331-3p 都参与了一些 PCa 中观察到的 erbB-2 的过表达。
