Department of Pathology, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA.
Leukemia. 2012 May;26(5):1064-72. doi: 10.1038/leu.2011.305. Epub 2011 Nov 25.
The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17∼92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P=0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17∼92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17∼92 cluster. Overexpression of miR-17∼92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17∼92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17∼92 cluster may therefore provide a novel therapeutic approach for patients with MCL.
套细胞淋巴瘤（MCL）患者的中位生存期为 3 至 5 年，采用目前的化疗方案。MCL 中常见的二次基因组改变是染色体 13q31-q32 获得/扩增，其靶向 microRNA（miRNA）簇 miR-17∼92。基于基因表达谱分析，我们发现这些 miRNA 的主要转录本 C13orf25 的高水平表达与 MCL 患者的生存较差相关（P=0.021）。我们证明，蛋白磷酸酶 PHLPP2 是 PI3K/AKT 通路的重要负调节剂，是 miR-17∼92 除了 PTEN 和 BIM 之外的直接靶标。miR-17∼92 簇过表达下调了 MCL 细胞中的这些蛋白。miR-17∼92 的过表达激活了 PI3K/AKT 通路，并抑制了 MCL 细胞系中化疗诱导的细胞凋亡。相反，抑制 miR-17∼92 的表达抑制了 PI3K/AKT 通路，并抑制了异种移植 MCL 小鼠模型中的肿瘤生长。因此，靶向 miR-17∼92 簇可能为 MCL 患者提供一种新的治疗方法。
