Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
Oncogene. 2012 Dec 6;31(49):5081-9. doi: 10.1038/onc.2012.15. Epub 2012 Feb 6.
MicroRNAs are important regulators of gene expression in normal development and disease. miR-9 is overexpressed in several cancer forms, including brain tumours, hepatocellular carcinomas, breast cancer and Hodgkin lymphoma (HL). Here we demonstrated a relevance for miR-9 in HL pathogenesis and identified two new targets Dicer1 and HuR. HL is characterized by a massive infiltration of immune cells and fibroblasts in the tumour, whereas malignant cells represent only 1% of the tumour mass. These infiltrates provide important survival and growth signals to the tumour cells, and several lines of evidence indicate that they are essential for the persistence of HL. We show that inhibition of miR-9 leads to derepression of DICER and HuR, which in turn results in a decrease in cytokine production by HL cells followed by an impaired ability to attract normal inflammatory cells. Finally, inhibition of miR-9 by a systemically delivered antimiR-9 in a xenograft model of HL increases the protein levels of HuR and DICER1 and results in decreased tumour outgrowth, confirming that miR-9 actively participates in HL pathogenesis and points to miR-9 as a potential therapeutic target.
MicroRNAs 是正常发育和疾病中基因表达的重要调节因子。miR-9 在多种癌症形式中过表达，包括脑肿瘤、肝细胞癌、乳腺癌和霍奇金淋巴瘤（HL）。在这里，我们证明了 miR-9 在 HL 发病机制中的相关性，并鉴定了两个新的靶标 Dicer1 和 HuR。HL 的特征是肿瘤中有大量免疫细胞和成纤维细胞浸润，而恶性细胞仅占肿瘤质量的 1%。这些浸润物为肿瘤细胞提供了重要的生存和生长信号，有几条证据表明它们对 HL 的持续存在至关重要。我们表明，抑制 miR-9 导致 DICER 和 HuR 的去抑制，这反过来又导致 HL 细胞产生细胞因子减少，随后吸引正常炎症细胞的能力受损。最后，在 HL 的异种移植模型中，通过系统递送的抗 miR-9 抑制 miR-9 会增加 HuR 和 DICER1 的蛋白水平，并导致肿瘤生长减少，证实 miR-9 积极参与 HL 的发病机制，并指出 miR-9 是一个潜在的治疗靶点。
