Down-regulated microRNA-375 expression as a predictive biomarker in non-small cell lung cancer brain metastasis and its prognostic significance.

ABSTRACT

Brain metastases (BM) are common among patients with non-small cell lung cancer (NSCLC) and have been associated with significant morbidity and limited survival. Early and sensitive detection of BM is essential for improving prognosis. Recently, microRNA-375(miR-375) which is specifically expressed in the brain has been found significantly dysregulated in many human cancers. However, there is still no data whether miR-375 is associated with higher risk of BM development in NSCLC. In this study, we detected the miR-375 expression using quantitative real-time PCR (qRT-PCR) and assessed its predictive and prognostic significance. Our result showed that miR-375 expression was significantly down-regulated in NSCLC patients with BM(BM+, N=30) compared with NSCLC without BM(BM-, N=30) (P<0.001). Statistical analysis indicated that low miR-375 expression was linked to advanced disease stage (P<0.001) and brain metastasis (P<0.001) in NSCLC patient. Survival analysis suggested that low-expression group had significantly shorter overall survival than high-expression group in NSCLC patients with BM(log-rank test P<0.05) as well as the total cases(log-rank test P<0.01). Multivariate Cox proportional hazards model analysis indicated that low miR-375 expression was independently linked to poor survival of patients with NSCLC (HR=5.48, 95% CI 1.93-15.56, P=0.001). In addition, we found that VEGF and MMP-9 were over-expressed in down-regulated miR-375 expression cases. Collectively, this study demonstrated that miR-375 may play an important role as a predictive biomarker in brain metastasis and an independent prognostic factor in NSCLC. Over-expression of VEGF and MMP-9 may be the reason for poor prognosis of NSCLC patients with low miR-375 expression.