A novel lncRNA NR4A1AS up-regulates orphan nuclear receptor NR4A1 expression by blocking UPF1-mediated mRNA destabilization in colorectal cancer

• DOI: 10.1042/cs20181061
• Publication Date: 2019-06-28T15:54:00Z
• Authors: Xina Xie; Jiatian Lin; Jianlan Liu; Meihui Huang; Yuantang Zhong; Bin Liang; Xuhong Song; Songgang Gu; Xiaolan Chang; Dongyang Huang; Aifa Tang
• Keywords: Male; 0301 basic medicine; Mice, Inbred BALB C; RNA Stability; Mice, Nude; Apoptosis; Cell Cycle Checkpoints; HCT116 Cells; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Cell Movement; Nuclear Receptor Subfamily 4, Group A, Member 1; Animals; Humans; Neoplasm Invasiveness; RNA, Long Noncoding; RNA, Messenger; Caco-2 Cells; Colorectal Neoplasms; RNA Helicases; Cell Proliferation; Signal Transduction

Abstract Long non-coding RNAs (lncRNAs) play important roles in tumorigenesis and cancer progression. The orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) acts as an oncogene, and is involved in colorectal cancer (CRC) development. However, the mechanism through which lncRNA regulates NR4A1 expression remains unknown. We aimed to identify lncRNAs that regulate NR4A1 and assess their underlying mechanisms in CRC. We first identified an antisense lncRNA of NR4A1 that was up-regulated in CRC tissues and cells with rapid amplification of cDNA ends (RACE), and designated it as NR4A1AS. Spearman correlation analysis showed that NR4A1AS was positively correlated with NR4A1 mRNA levels in 37 CRC tissues. Mechanistically, NR4A1AS stabilized NR4A1 mRNA by forming RNA–RNA complexes via partial base-pairing and up-regulated NR4A1 expression in CRC cells. RNA immunoprecipitation (RIP) assays revealed that knockdown of NR4A1AS expression by siRNA enhanced up-frameshift 1 (UPF1) recruitment to NR4A1 mRNA, thereby decreasing NR4A1 mRNA stability. Moreover, depletion of NR4A1AS was found to mimic the effect of NR4A1 knockdown, specifically by suppressing cell proliferation, migration and invasion, and inducing apoptosis and cell cycle arrest. Accordingly, restoring NR4A1 expression ameliorated the effects of NR4A1AS knockdown on tumor growth and metastasis of CRC cells in vitro and in vivo. Thus, we conclude that NR4A1AS up-regulates NR4A1 expression by forming RNA–RNA complexes and blocking UPF1-mediated mRNA destabilization, and it functions in tumor growth and metastasis of CRC cells at least partly through regulating NR4A1, suggesting that NR4A1AS might be as a potential target for RNA-based anti-CRC drug studies.