文章：

微小RNA调控弥漫大B细胞淋巴瘤进展过程中的关键细胞存活通路，并介导化疗敏感性

MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma

原文发布日期：2017-12-15

DOI: 10.1038/s41408-017-0033-8

类型: Article

开放获取: 是

英文摘要：

Despite better therapeutic options and improved survival of diffuse large B-cell lymphoma (DLBCL), 30–40% of the patients experience relapse or have primary refractory disease with a dismal prognosis. To identify biological correlates for treatment resistance, we profiled microRNAs (miRNAs) of matched primary and relapsed DLBCL by next-generation sequencing. Altogether 492 miRNAs were expressed in the DLBCL samples. Thirteen miRNAs showed significant differential expression between primary and relapse specimen pairs. Integration of the differentially expressed miRNAs with matched mRNA expression profiles identified highly anti-correlated, putative targets, which were significantly enriched in cancer-associated pathways, including phosphatidylinositol (PI)), mitogen-activated protein kinase (MAPK), and B-cell receptor (BCR) signaling. Expression data suggested activation of these pathways during disease progression, and functional analyses validated that miR-370-3p, miR-381-3p, and miR-409-3p downregulate genes on the PI, MAPK, and BCR signaling pathways, and enhance chemosensitivity of DLBCL cells in vitro. High expression of selected target genes, that is, PIP5K1 and IMPA1, was found to be associated with poor survival in two independent cohorts of chemoimmunotherapy-treated patients (n = 92 and n = 233). Taken together, our results demonstrate that differentially expressed miRNAs contribute to disease progression by regulating key cell survival pathways and by mediating chemosensitivity, thus representing potential novel therapeutic targets.

摘要翻译： 

尽管弥漫性大B细胞淋巴瘤（DLBCL）的治疗方案有所改进且患者生存率提高，但仍有30%-40%的患者经历复发或患有原发性难治性疾病，预后不良。为识别治疗耐药性的生物学相关性，我们通过新一代测序技术对匹配的原发性和复发性DLBCL样本进行了微RNA（miRNA）分析。DLBCL样本中总共表达了492种miRNA，其中13种miRNA在原发与复发配对样本中呈现显著差异表达。通过整合差异表达的miRNA与匹配的mRNA表达谱，我们发现了高度负相关的推定靶基因，这些基因在癌症相关通路中显著富集，包括磷脂酰肌醇（PI）、丝裂原活化蛋白激酶（MAPK）和B细胞受体（BCR）信号通路。表达数据提示这些通路在疾病进展中被激活，功能分析验证了miR-370-3p、miR-381-3p和miR-409-3p能下调PI、MAPK和BCR信号通路上的基因，并在体外增强DLBCL细胞的化学敏感性。在两组接受化学免疫疗法治疗的独立患者队列（n=92和n=233）中，特定靶基因（即PIP5K1和IMPA1）的高表达与不良生存率相关。综上，我们的研究结果表明，差异表达的miRNA通过调控关键细胞生存通路和介导化学敏感性促进疾病进展，因此代表了潜在的新型治疗靶点。

原文链接：

MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma