Mizuno Keiko, Mataki Hiroko, Arai Takayuki, Okato Atsushi, Kamikawaji Kazuto, Kumamoto Tomohiro, Hiraki Tsubasa, Hatanaka Kazuhito, Inoue Hiromasa, Seki Naohiko
Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan.
J Hum Genet. 2017 Jul;62(7):671-678. doi: 10.1038/jhg.2017.27. Epub 2017 Mar 9.
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.
小细胞肺癌（SCLC）约占所有确诊肺癌的15%。SCLC是一种特别致命的恶性肿瘤，因为经过适当治疗后的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，需要为这些患者制定新的治疗策略。SCLC细胞侵袭性及其耐药性产生的分子机制仍不明确。在本研究中，我们通过分析尸检标本新构建了SCLC的微小RNA（miRNA）表达特征。基于所得特征，发现四种miRNA（miR-27a-5p、miR-485-3p、miR-34-5p和miR-574-3p）为候选抗肿瘤miRNA。为了研究它们的功能重要性，我们首先在SCLC临床标本中验证了miR-27a-5p和miR-34b-3p的下调。接下来，我们证明miR-27a-5p和miR-34b-3p的异位表达均显著抑制癌细胞侵袭性。我们的计算机分析表明，四个基因（拓扑异构酶2α（TOP2A）、母源胚胎亮氨酸拉链激酶（MELK）、着丝粒蛋白F（CENPF）和SRY盒1（SOX1））被确定为miR-27a-5p和miR-34b-3p调控的基因。基于免疫组织化学分析，TOP2A、MELK和CENPF参与了SCLC的发病机制。这些基因可能促成了SCLC细胞的高增殖和早期转移扩散。基于SCLC特征阐明差异表达的miRNA介导的癌症通路可能为SCLC发病机制提供新的见解。
