Abstract
BackgroundNon-small cell lung cancer (NSCLC) is a leading cause of death worldwide. MicroRNAs (miRNAs) have been indicated as crucial actors in cancer biology. Accumulating evidence suggests that miRNAs can be used as diagnostic and prognostic markers for NSCLC.MethodsThe purpose of this study was to characterize and identify the novel biomarker miR-4317 and its targets in NSCLC. The expression of miR-4317 was analyzed by in situ hybridization (ISH) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of miR-4317 on proliferation was evaluated through 3–4,5-dimethylthiazol-2-yl-5-3–carboxymethoxyphenyl-2-4-sulfophenyl-2H-tetrazolium (MTS) and colony formation assays, and cell migration and invasion were evaluated through transwell assays. The expression of target proteins and downstream molecules was analyzed by qRT-PCR and western blot. Dual-luciferase reporter assay was used to assess the target genes of miR4317 in NSCLC cells.ResultsOur results demonstrated that miR-4317 was downregulated in NSCLC tissues and serum, particularly in lymph node metastasis and advanced clinical stage tissues. Kaplan-Meier survival analysis showed that NSCLC patients with high expression of miR-4317 exhibited better overall survival (OS). Enhanced expression of miR-4317 significantly inhibited proliferation, colony formation, migration and invasion, and hampered cycles of NSCLC cell lines in vitro. Our results suggested that miR-4317 functions by directly targeting fibroblast growth factor 9 (FGF9) and cyclin D2 (CCND2). In concordance with in vitro studies, mouse xenograft, lung, and brain metastatic studies validated that miR-4317 functions as a potent suppressor miRNA of NSCLC in vivo. Systemically delivered agomiR-4317 reduced tumor growth and inhibited FGF9 and CCND2 protein expression. Reintroduction of FGF9 and CCND2 attenuated miR-4317-mediated suppression of migration and invasion in NSCLC.ConclusionsOur results indicate that miR-4317 can reduce NSCLC cell growth and metastasis by targeting FGF9 and CCND2. These findings provide new evidence of miR-4317 as a potential non-invasive biomarker and therapeutic target for NSCLC.
Highlights
Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide
Identification of miR-4317 in NSCLC To identify miRNAs associated with overall survival (OS) in lung adenocarcinoma, we analyzed miRNA expression profiles in formalin-fixed paraffin-embedded specimens of 87 lung adenocarcinoma patients according to the expression level of each miRNA among 309 detected human microRNAs
A lower level of miR-4317 was detected in advanced clinical stages and during lymph node metastasis compared with early clinical stages and in the presence of non-metastatic lymph nodes (p < 0.003; Table 1)
Summary
Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Classical approaches to cloning have partially revealed miRNA expression profiles in a panel of mammalian tissues and cell types [8, 9], low throughput, low sensitivity, and poor resolution make these approaches unlikely to define the miRNome. Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-associated death both in men and women worldwide [10]. 85% of lung cancers are classified histopathologically as non-small cell lung carcinomas (NSCLCs) [12]. The poor outcomes and frequent relapses associated with lung cancer urgently demand the development of new screening methods and early biomarkers for accurate and non-invasive detection of lung cancer metastasis and recurrence [15, 16]. There is a great need for the development of strategies for improved diagnosis, prevention, and therapy for NSCLC
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