Abstract
Long noncoding RNA differentiation antagonizing nonprotein coding RNA (lncRNA-DANCR) is associated with poor prognosis in multiple cancers, and promotes cancer stemness and invasion. However, the exact mechanisms by which DANCR promotes non-small cell lung cancer (NSCLC) remain elusive. In this study, we determined that DANCR knockdown (KD) impeded cell migration and reduced stem-like characteristics in two NSCLC cell lines, A549 and H1755. Wnt signaling was shown to promote NSCLC proliferation, stemness, and invasion; therefore, we hypothesized that DANCR may regulate these activities through induction of the Wnt/β-catenin pathway. DANCR KD reduced β-catenin signaling and protein expression, and decreased the expression of β-catenin gene targets c-Myc and Axin2. One of the well-defined functions of lncRNAs is their ability to bind and inhibit microRNAs. Through in silico analysis, we identified tumor suppressor miR-216a as a potential binding partner to DANCR, and confirmed this binding through coimmunoprecipitation and luciferase-reporter assays. Furthermore, we show that DANCR-induced β-catenin protein expression may be blocked with miR-216a overexpression. Our findings illustrate a role of DANCR in NSCLC migration and stemness, and suggest a novel DANCR/miR-216a signaling axis in the Wnt/β-catenin pathway.
Highlights
Lung cancer is the leading global cause of cancer-related deaths
In order to illuminate the molecular mechanisms that promote Non-small cell lung cancer (NSCLC) progression, we examined The Cancer Genome Atlas (TCGA) dataset for differentiation-antagonizing nonprotein-coding RNA (DANCR) expression in the most common NSCLC subtypes: lung adenocarcinoma (n = 706) and lung squamous cell carcinoma (n = 626)
We further examined DANCR expression in NSCLC adenocarcinoma cell lines A549, H1975, H1755, H1944, H2087, and H358, and NSCLC large cell carcinoma cell lines H661 and H1299, and found that DANCR was significantly increased in 7 of the 8 NSCLC cell lines compared to human bronchial epithelial cell line HBE2 (Figure 1B)
Summary
Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancer cases [1]. Despite advancements in therapy for early-stage NSCLC, the five-year relative survival rate of NSCLC remains at 23% because the majority of patients are diagnosed at advanced stages, when cancer cells have already metastasized [1]. Further investigation on the mechanisms of NSCLC progression is necessary to improve patient outcomes. Noncoding RNAs (ncRNAs) are critical regulators of gene expression that are commonly dysregulated in cancer. MicroRNAs (miRNAs) are small ncRNAs that are 16–24 nucleotides long, and function post-transcriptionally by binding to target mRNAs at specific recognition sequences, leading to target mRNA degradation or translational repression. MiR-216a was described as an inhibitor of NSCLC cell growth, invasion, and metastasis [3]. The direct mechanism by which miR-216a expression is regulated in NSCLC has not been defined
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