Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from never smokers.
Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from never smokers.
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DOI：
10.1158/1078-0432.ccr-11-2857
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发表时间：
2012-07-01
期刊：
影响因子：
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通讯作者：
Jen J
中科院分区：
文献类型：
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作者：
Jang JS;Jeon HS;Sun Z;Aubry MC;Tang H;Park CH;Rakhshan F;Schultz DA;Kolbert CP;Lupu R;Park JY;Harris CC;Yang P;Jen J
microRNA在人类疾病和癌症中起着重要作用。我们试图研究microRNA在非小细胞肺癌中的表达状态、临床相关性和功能作用。我们使用56对新鲜冷冻（FF）和47对来自从不吸烟者的福尔马林固定石蜡包埋（FFPE）样本在匹配的肺腺癌和未受累肺中进行了miRNA表达谱分析。采用考克斯分析和Log-Rank检验对差异表达的miRNA基因进行分析。在最佳候选者中，进一步检查miR-708在两个独立群组中的差异表达。通过鉴定其候选mRNA靶点并通过操纵其在培养细胞中的表达水平来检查肺癌中miR-708表达的功能意义。在测试的肿瘤和正常样品之间最差异表达的20种miRNAs中，在校正所有临床显著因素（包括年龄、性别和肿瘤分期）后，肿瘤中miR-708的高表达水平与死亡风险增加最强相关。（FF队列：HR，1.90; 95% CI，1.08-3.35; P=.025; FFPE队列：HR，1.93; 95% CI，1.02-3.63; P=.042）。TMEM 88基因的转录物在其3′ UTR中具有miR-708结合位点，并且在miR-708高的肿瘤中显著减少。强制miR-708表达降低了TMEM 88转录水平，并增加了培养物中细胞增殖、侵袭和迁移的速率。MicroRNA-708作为致癌基因，通过直接下调TMEM 88（肺癌中Wnt信号通路的负调节因子），促进肿瘤生长和疾病进展。
MicroRNA plays an important role in human diseases and cancer. We seek to investigate the expression status, clinical relevance, and functional role of microRNA in non-small cell lung cancer. We performed miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen (FF) and 47 pairs of formalin-fixed, paraffin-embedded (FFPE) samples from never smokers. The most differentially expressed miRNA genes were evaluated by Cox analysis and Log-Rank test. Among the best candidate, miR-708 was further examined for differential expression in two independent cohorts. Functional significance of miR-708 expression in lung cancer was examined by identifying its candidate mRNA target and through manipulating its expression levels in cultured cells. Among the 20 miRNAs most differentially expressed between tested tumor and normal samples, high expression level of miR-708 in the tumors was most strongly associated with an increased risk of death after adjustments for all clinically significant factors including age, sex, and tumor stage (FF cohort: HR, 1.90; 95% CI, 1.08-3.35; P=.025 and FFPE cohort: HR, 1.93; 95% CI, 1.02-3.63; P=.042). The transcript for TMEM88 gene has a miR-708 binding site in its 3′ UTR and was significantly reduced in tumors high of miR-708. Forced miR-708 expression reduced TMEM88 transcript levels and increased the rate of cell proliferation, invasion, and migration in culture. MicroRNA-708 acts as an oncogene contributing to tumor growth and disease progression by directly down regulating TMEM88, a negative regulator of the Wnt signaling pathway in lung cancer.