MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma.
MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma.
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DOI：
10.1038/s41408-017-0033-8
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发表时间：
2017-12-15
影响因子：
12.8
通讯作者：
Leppä S
中科院分区：
文献类型：
--
作者：
Leivonen SK;Icay K;Jäntti K;Siren I;Liu C;Alkodsi A;Cervera A;Ludvigsen M;Hamilton-Dutoit SJ;d'Amore F;Karjalainen-Lindsberg ML;Delabie J;Holte H;Lehtonen R;Hautaniemi S;Leppä S
尽管弥漫性大B细胞淋巴瘤（DLBCL）有更好的治疗选择和改善的生存率，但30-40%的患者会复发或患有原发性难治性疾病，预后不良。为了确定治疗抗性的生物学相关性，我们通过下一代测序分析了匹配的原发性和复发性DLBCL的microRNA（miRNA）。在DLBCL样本中总共表达了492个miRNA。13个miRNAs在原发和复发标本对之间显示出显著的差异表达。差异表达的miRNA与匹配的mRNA表达谱的整合鉴定了高度反相关的推定靶点，其在癌症相关途径中显著富集，包括磷脂酰肌醇（PI）、促分裂原活化蛋白激酶（MAPK）和B细胞受体（BCR）信号传导。表达数据表明这些途径在疾病进展期间被激活，并且功能分析验证了miR-370- 3 p、miR-381- 3 p和miR-409- 3 p下调PI、MAPK和BCR信号传导途径上的基因，并增强DLBCL细胞的体外化学敏感性。在两个独立的接受化学免疫疗法治疗的患者队列中，发现所选靶基因（即PIP 5 K1和IMPA 1）的高表达与不良生存率相关（n = 92和n = 233）。总之，我们的研究结果表明，差异表达的miRNA通过调节关键细胞存活途径和介导化疗敏感性促进疾病进展，因此代表了潜在的新治疗靶点。
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.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
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影响因子：
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影响因子：
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影响因子：
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作者：
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