Abstract
Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer-related death worldwide. Although many molecular-targeted drugs for NSCLC have been developed in recent years, the 5-year survival rate of patients with NSCLC remains low. Therefore, an improved understanding of the molecular mechanisms underlying the biology of NSCLC is essential for developing novel therapeutic strategies for the treatment of NSCLC. In this study, we examined the role of miR-130b in NSCLC. Our results showed that high expression of miR-130b in clinical specimens was significantly associated with poor overall survival in patients with NSCLC. Moreover, miR-130b expression was significantly increased in NSCLC clinical specimens from patients with vascular and lymphatic invasion. Consistent with this, overexpression of miR-130b promoted invasion and matrix metalloproteinase-2 (MMP-2) activity in A549 cells. Argonaute2 immunoprecipitation and gene array analysis identified tissue inhibitor of metalloproteinase-2 (TIMP-2) as a target of miR-130b. Invasion activity promoted by miR-130b was attenuated by TIMP-2 overexpression in A549 cells. Furthermore, TIMP-2 concentrations in serum were inversely correlated with relative miR-130b expression in tumor tissues from the same patients with NSCLC. Overall, miR-130b was found to act as an oncomiR, promoting metastasis by downregulating TIMP-2 and invasion activities in NSCLC cells.
Highlights
Lung cancer is the most common cause of cancer-related death worldwide, causing an estimated 1.6 million deaths each year
Using The Cancer Genome Atlas (TCGA) database, we first investigated the relationship between expression of the miR-130 family and prognosis of patients with non-small cell lung cancer (NSCLC)
In the present study, based on the significant correlation between high miR-130b expression and poor overall survival in patients with NSCLC, we demonstrated that miR-130b increased invasion activity by directly targeting tissue inhibitor of metalloproteinase (TIMP)-2 in adenocarcinoma cells and in squamous cell carcinoma cells using loss-of function and gain-of function experiments
Summary
Lung cancer is the most common cause of cancer-related death worldwide, causing an estimated 1.6 million deaths each year. Several therapeutic agents for NSCLC have been developed, the prognosis of patients with NSCLC is still poor, and the 5-year survival rate is less than 18% This low survival rate may be explained by the observation that most cases are diagnosed as a late stage, when lung cancer cells have already metastasised to distant organs[3,4,5]. MicroRNAs (miRNAs) are small noncoding RNA molecules 20–25 nucleotides in length These molecules regulate gene expression through translational repression or degradation of mRNA by binding to the 3′-untranslated region (3′-UTR) of target mRNAs16. Because 30–60% of human genes can be regulated by miRNAs19,20, these molecules have the potential to modulate various cellular processes, such as cell growth, migration, invasion, apoptosis, and angiogenesis[21]. MiR-130 family-targeted LNA oligonucleotides were found to suppress tumor growth in an in vivo xenograft model[23]
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