Long non-coding RNA BRE-AS1 represses non-small cell lung cancer cell growth and survival via up-regulating NR4A3.

ABSTRACT

Recently, several long non-coding RNAs (lncRNAs) have been revealed to play crucial roles in tumorigenesis and progression of many cancers. Nevertheless, more than 50,000 lncRNAs were identified in human cells and the roles of majority of these lncRNAs in non-small cell lung cancer (NSCLC) are unknown. In this study, using public NSCLC microarray data we identified a novel lncRNA BRE antisense RNA 1 (BRE-AS1). BRE-AS1 is significantly down-regulated in NSCLC tissues and cell lines. Gain-of-function and loss-of-function assays showed that BRE-AS1 reduces NSCLC cell viability, represses NSCLC cell proliferation, and induces NSCLC cell apoptosis in vitro, and represses NSCLC tumor growth in vivo. Mechanistic investigation revealed that BRE-AS1 physically binds STAT3, reduces the binding of STAT3 to the promoter of NR4A3, relieves the repression of NR4A3 caused by STAT3, and up-regulates NR4A3 expression. Consistently, NR4A3 is significantly down-regulated in NSCLC tissues and the expression of NR4A3 is positively correlated with the expression of BRE-AS1 in NSCLC tissues. In addition, depletion of NR4A3 attenuates the tumor suppressive roles of BRE-AS1 in NSCLC. Collectively, our data demonstrate that BRE-AS1 represses NSCLC cell growth and survival via up-regulating NR4A3 and suggest that enhancing BRE-AS1 may be potential therapeutic strategy for NSCLC.