miR-141和miR-200c作为早期非小细胞肺癌腺癌总生存期的标志物。
miR-141 and miR-200c as markers of overall survival in early stage non-small cell lung cancer adenocarcinoma.
作者信息
Tejero Rut, Navarro Alfons, Campayo Marc, Viñolas Nuria, Marrades Ramon M, Cordeiro Anna, Ruíz-Martínez Marc, Santasusagna Sandra, Molins Laureano, Ramirez Josep, Monzó Mariano
机构信息
Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
Department of Medical Oncology, Institut Clinic Malalties Hemato-Oncològiques (ICMHO), Hospital Clinic de Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain.
出版信息
PLoS One. 2014 Jul 8;9(7):e101899. doi: 10.1371/journal.pone.0101899. eCollection 2014.
BACKGROUND
Several treatments in non-small cell lung cancer (NSCLC) are histology-dependent, and the need for histology-related markers is increasing. MicroRNAs (miRNAs) are promising molecular markers in multiple cancers and show differences in expression depending on histological subtype. The miRNA family miR-200 has been associated with the regulation of epithelial-mesenchymal (EMT)/mesenchymal-epithelial transition (MET). EMT involves profound phenotypic changes that include the loss of cell-cell adhesion, the loss of cell polarity, and the acquisition of migratory and invasive properties that facilitates metastasis. A dual role for the miR-200 family in the prognosis of several tumors has been related to tumor cell origin. However, the prognostic role and function of miR-200 family in early-stage NSCLC adenocarcinoma and squamous cell carcinoma (SCC) have not been well established.
METHODS
miRNA expression was determined using TaqMan assays in 155 tumors from resected NSCLC patients. Functional studies were conducted in three NSCLC cell lines: H23, A-549 and HCC-44.
RESULTS
High miR-200c expression was associated with shorter overall survival (OS) in the entire cohort (p = 0.024). High miR-200c (p = 0.0004) and miR-141 (p = 0.009) expression correlated with shorter OS in adenocarcinoma - but not in SCC. In the multivariate analysis, a risk score based on miR-141 and miR-200c expression emerged as an independent prognostic factor for OS in the entire cohort (OR, 2.787; p = 0.033) and in adenocarcinoma patients (OR, 10.649; p = 0.002). Functional analyses showed that miR-200c, was related to mesenchymal-epithelial transition (MET) and affected cell migration and E-cadherin levels, while overexpression of miR-141 reduced KLF6 protein levels and produced an increase of secretion of VEGFA in vitro (H23, p = 0.04; A-549, p = 0.03; HCC-44, p = 0.02) and was associated with higher blood microvessel density in patient tumor samples (p<0.001).
CONCLUSION
High miR-141 and miR-200c expression are associated with shorter OS in NSCLC patients with adenocarcinoma through MET and angiogenesis.
背景
非小细胞肺癌（NSCLC）的几种治疗方法取决于组织学类型，对组织学相关标志物的需求也在增加。微小RNA（miRNA）是多种癌症中很有前景的分子标志物，其表达因组织学亚型而异。miR-200 miRNA家族与上皮-间质转化（EMT）/间质-上皮转化（MET）的调节有关。EMT涉及深刻的表型变化，包括细胞间粘附丧失、细胞极性丧失以及获得促进转移的迁移和侵袭特性。miR-200家族在几种肿瘤预后中的双重作用与肿瘤细胞起源有关。然而，miR-200家族在早期NSCLC腺癌和鳞状细胞癌（SCC）中的预后作用和功能尚未完全明确。
方法
使用TaqMan分析法测定了155例接受手术切除的NSCLC患者肿瘤中的miRNA表达。在三种NSCLC细胞系（H23、A-549和HCC-44）中进行了功能研究。
结果
在整个队列中，高miR-200c表达与较短的总生存期（OS）相关（p = 0.024）。高miR-200c（p = 0.0004）和miR-141（p = 0.009）表达与腺癌患者较短的OS相关，但与SCC患者无关。在多变量分析中，基于miR-141和miR-200c表达的风险评分成为整个队列（OR，2.787；p = 0.033）和腺癌患者（OR，10.649；p = 0.002）OS的独立预后因素。功能分析表明，miR-200c与间质-上皮转化（MET）相关，并影响细胞迁移和E-钙粘蛋白水平，而miR-141的过表达降低了KLF6蛋白水平，并在体外增加了VEGFA的分泌（H23，p = 0.04；A-549，p = 0.03；HCC-44，p = 0.02），并且与患者肿瘤样本中较高的微血管密度相关（p<0.001）。
结论
高miR-141和miR-200c表达通过MET和血管生成与NSCLC腺癌患者较短的OS相关。
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