LncRNA CEBPA-DT promotes liver cancer metastasis through DDR2/β-catenin activation via interacting with hnRNPC

Abstract

Background Hepatocellular carcinoma (HCC) is the world’s third leading cause of cancer-related death; due to the fast growth and high prevalence of tumor recurrence, the prognosis of HCC patients remains dismal. Long non-coding RNA CEBPA-DT, a divergent transcript of the CCAAT Enhancer Binding Protein Alpha (CEBPA) gene, has been shown to participate in multiple tumor progression. However, no research has established its cancer-promoting mechanism in HCC yet. Methods CEBPA-DT was identified in human HCC tissues through RNA sequencing. The expression level of CEBPA-DT was assessed by quantitative real-time PCR. The biological effects of CEBPA-DT were evaluated in vitro and in vivo through gain or loss of function experiments. RNA fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were applied to investigate the downstream target of CEBPA-DT. Immunofluorescence, subcellular protein fractionation, western blot, and co-immunoprecipitation were performed to analyze the subcellular location of β-catenin and its interaction with Discoidin domain-containing receptor 2 (DDR2). Results CEBPA-DT was upregulated in human HCC tissues with postoperative distant metastasis and intimately related to the worse prognosis of HCC patients. Silencing of CEBPA-DT inhibited the growth, migration and invasion of hepatoma cells in vitro and in vivo, while enhancement of CEBPA-DT played a contrasting role. Mechanistic investigations demonstrated that CEBPA-DT could bind to heterogeneous nuclear ribonucleoprotein C (hnRNPC), which facilitated cytoplasmic translocation of hnRNPC, enhanced the interaction between hnRNPC and DDR2 mRNA, subsequently promoted the expression of DDR2. Meanwhile, CEBPA-DT induced epithelial-mesenchymal transition (EMT) process through upregulation of Snail1 via facilitating nuclear translocation of β-catenin. Using DDR2 inhibitor, we revealed that the CEBPA-DT induced the interaction between DDR2 and β-catenin, thus promoting the nuclear translocation of β-catenin to activate transcription of Snail1, contributing to EMT and HCC metastasis. Conclusions Our results suggested that CEBPA-DT promoted HCC metastasis through DDR2/β-catenin mediated activation of Snail1 via interaction with hnRNPC, indicating that the CEBPA-DT-hnRNPC-DDR2/β-catenin axis may be used as a potential therapeutic target for HCC treatment.

LncRNA CHKB-DT Downregulation Enhances Dilated Cardiomyopathy Through ALDH2

“…Considering that lncRNAs typically regulate target genes through interactions with RBPs, 30 we further identified CHKB-DT-interacting proteins. RAP-MS assays showed that FUS was a binding partner of CHKB-DT, while lncRNA CHKB-DT was predicted containing several FUS-binding sites.…”

Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription

“…For instance, LncRNA CEBPA-DT is upregulated in human HCC tissues with distant metastasis after surgery and is closely associated with poorer prognosis in HCC patients. A mechanistic study showed that CEBPA-DT can bind to heteroribonucleoprotein C (hnRNPC), promote the cytoplasmic translocation of hnRNPC, enhance the interaction between hnRNPC and DDR2 mRNA, and then promote the expression of DDR2[ 27 ]. Moreover, Wang et al [ 28 ] indicated that the expression of LINC00665 is upregulated in gastric cancer tissues and is associated with poor prognosis in patients with gastric cancer.…”

Noncoding RNAs in Hepatocellular Carcinoma: Potential Applications in Combined Therapeutic Strategies and Promising Candidates of Treatment Response

“…To give a couple of examples, the lncRNA CEBPA-DT is upregulated in HCC with distant metastasis and is associated with poor prognosis. Cai et al demonstrated that CEBPA-DT induced the epithelial-mesenchymal transition (EMT) through the upregulation of Snail1 by promoting the nuclear translocation of β-catenin [20]. Similarly, the lncRNA FTO-IT1 is overexpressed in HCC, and it emerged as a glycolysis-associated lncRNA influencing the metabolic shift of cancer cells by increasing their glycolytic capacity and proliferation rate.…”