Abstract
BackgroundSeveral 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.MethodsmiRNA 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.ResultsHigh 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).ConclusionHigh miR-141 and miR-200c expression are associated with shorter OS in NSCLC patients with adenocarcinoma through MET and angiogenesis.
Highlights
Lung cancer is the most common cause of cancer death, with more than 226,000 new cases in the United States in 2012 [1]
Different mechanisms are involved in the effect of these miRNAs; while miR-141 seems to act through angiogenesis by inhibiting KLF6 and increasing VEGFA levels, miR-200c plays a role in the regulation of mesenchymal-epithelial transition (MET)
In order to investigate if the regulation of MET by miR-141 and miR-200c was histologydependent, we examined their prognostic value in the two major histological subtypes and found both miR-141 and miR-200c were related to overall survival (OS) only in adenocarcinoma patients
Summary
Lung cancer is the most common cause of cancer death, with more than 226,000 new cases in the United States in 2012 [1]. Eighty percent of lung cancers are non-small-cell lung cancer (NSCLC) [2], which has a 5-year survival of only 10% overall and 60–70% in stage I patients, highlighting the need for novel diagnostic and therapeutic strategies. Several novel treatments in NSCLC are histology-dependent, and squamous cell carcinoma (SCC) responds somewhat differently than adenocarcinoma to certain treatment regimens[3,4] [5]. Few histology-dependent prognostic biomarkers are available for routine use in clinical practice, especially in resectable patients. Several treatments in non-small cell lung cancer (NSCLC) are histology-dependent, and the need for histologyrelated markers is increasing. The prognostic role and function of miR-200 family in early-stage NSCLC adenocarcinoma and squamous cell carcinoma (SCC) have not been well established
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