The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes
The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes
复制标题
DOI：
10.1038/jhg.2017.27
复制
发表时间：
2017-07-01
影响因子：
3.5
通讯作者：
Seki, Naohiko
中科院分区：
文献类型：
--
作者：
Mizuno, Keiko;Mataki, Hiroko;Seki, Naohiko
小细胞肺癌（SCLC）约占所有诊断肺癌的15%。SCLC是一种特别致命的恶性肿瘤，经过适当治疗后的2年生存率低于5%。SCLC患者尚未从最近开发的分子靶向治疗中获益。因此，需要一种新的治疗策略。SCLC细胞侵袭性及其耐药发展的分子机制尚不清楚。在这项研究中，我们通过分析尸检标本，新构建了SCLC的microRNA （miRNA）表达特征。基于由此产生的特征，发现四个mirna （miR-27a-5p, miR-485-3p， miR-34-5p和miR-574-3p）是候选抗肿瘤mirna。为了研究它们的功能重要性，我们首先验证了在SCLC临床标本中miR-27a-5p和miR-34b-3p的下调。接下来，我们证明了miR-27a-5p和miR-34b-3p的异位表达显著抑制了癌细胞的侵袭性。我们的计算机分析显示，四个基因(拓扑异构酶2 α （TOP2A)、母胚亮氨酸拉链激酶（MELK）、着丝粒蛋白F （CENPF）和SRY-box 1 (SOX1)）被鉴定为mir -27a-5p和mir -34b-3p调控基因。免疫组化分析表明，TOP2A、MELK和CENPF参与了SCLC的发病机制。这些基因可能有助于SCLC细胞的高增殖和早期转移扩散。基于SCLC特征的差异表达的mirna介导的癌症途径的阐明可能为SCLC的发病机制提供新的见解。
Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous. In this study, we newly constructed a microRNA (miRNA) expression signature of SCLC by analysis of autopsy specimens. Based on the resultant signature, four miRNAs (miR-27a-5p, miR-485-3p, miR-34-5p and miR-574-3p) were found to be candidate anti-tumor miRNAs. To investigate their functional importance, we first validated the downregulation of miR-27a-5p and miR-34b-3p in SCLC clinical specimens. Next, we demonstrated that ectopic expression of both miR-27a-5p and miR-34b-3p significantly inhibited cancer cell aggressiveness. Our in silico analyses showed that four genes (topoisomerase 2 alpha (TOP2A), maternal embryonic leucine zipper kinase (MELK), centromere protein F (CENPF) and SRY-box 1 (SOX1) were identified as miR-27a-5p-and miR-34b-3p-regulated genes. Based on immunohistochemical analysis, TOP2A, MELK and CENPF were involved in SCLC pathogenesis. These genes might contribute to high proliferation and early metastatic spread of SCLC cells. Elucidation of differentially expressed miRNA-mediated cancer pathways based on SCLC signature may provide new insights into the mechanisms of SCLC pathogenesis.