PMID- 36471363 OWN - NLM STAT- MEDLINE DCOM- 20221212 LR - 20221212 IS - 1756-9966 (Electronic) IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 41 IP - 1 DP - 2022 Dec 6 TI - LncRNA CEBPA-DT promotes liver cancer metastasis through DDR2/beta-catenin activation via interacting with hnRNPC. PG - 335 LID - 10.1186/s13046-022-02544-6 [doi] LID - 335 AB - 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 beta-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 beta-catenin. Using DDR2 inhibitor, we revealed that the CEBPA-DT induced the interaction between DDR2 and beta-catenin, thus promoting the nuclear translocation of beta-catenin to activate transcription of Snail1, contributing to EMT and HCC metastasis. CONCLUSIONS: Our results suggested that CEBPA-DT promoted HCC metastasis through DDR2/beta-catenin mediated activation of Snail1 via interaction with hnRNPC, indicating that the CEBPA-DT-hnRNPC-DDR2/beta-catenin axis may be used as a potential therapeutic target for HCC treatment. CI - (c) 2022. The Author(s). FAU - Cai, Yunshi AU - Cai Y AD - Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. AD - Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Lyu, Tao AU - Lyu T AD - Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. AD - Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Li, Hui AU - Li H AD - Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China. FAU - Liu, Chang AU - Liu C AD - Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. AD - Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Xie, Kunlin AU - Xie K AD - Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. AD - Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Xu, Lin AU - Xu L AD - Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Li, Wei AU - Li W AD - Department of Plastic and Burns Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Liu, Hu AU - Liu H AD - Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. FAU - Zhu, Jiang AU - Zhu J AD - Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. FAU - Lyu, Yinghao AU - Lyu Y AD - Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. FAU - Feng, Xuping AU - Feng X AD - Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China. FAU - Lan, Tian AU - Lan T AD - Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. blue_sky_land@163.com. AD - Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China. blue_sky_land@163.com. FAU - Yang, Jiayin AU - Yang J AD - Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. doctoryjy@scu.edu.cn. FAU - Wu, Hong AU - Wu H AD - Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. wuhong@scu.edu.cn. LA - eng GR - 81972747/Natural Science Foundation of China/ GR - 82173124/Natural Science Foundation of China/ PT - Journal Article DEP - 20221206 PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - 0 (beta Catenin) RN - 0 (CCAAT-Enhancer-Binding Protein-alpha) RN - 0 (CCAAT-Enhancer-Binding Proteins) RN - 0 (CEBPA protein, human) RN - EC 2.7.10.1 (DDR2 protein, human) RN - 0 (Heterogeneous-Nuclear Ribonucleoprotein Group C) RN - 0 (HNRNPC protein, human) RN - 0 (RNA, Long Noncoding) RN - 0 (CEBPA-DT long noncoding RNA, human) SB - IM MH - Humans MH - beta Catenin/genetics/metabolism MH - *Carcinoma, Hepatocellular/secondary MH - CCAAT-Enhancer-Binding Protein-alpha/genetics/metabolism MH - CCAAT-Enhancer-Binding Proteins/metabolism MH - Cell Line, Tumor MH - Cell Movement/genetics MH - Cell Proliferation/genetics MH - Epithelial-Mesenchymal Transition/genetics MH - Gene Expression Regulation, Neoplastic MH - Heterogeneous-Nuclear Ribonucleoprotein Group C/genetics MH - In Situ Hybridization, Fluorescence MH - *Liver Neoplasms/pathology MH - *RNA, Long Noncoding/genetics/metabolism PMC - PMC9724427 OTO - NOTNLM OT - CEBPA-DT OT - DDR2 OT - EMT OT - Hepatocellular carcinoma OT - hnRNPC OT - beta-catenin COIS- The authors have declared no conflict of interest. EDAT- 2022/12/06 06:00 MHDA- 2022/12/15 06:00 PMCR- 2022/12/06 CRDT- 2022/12/05 23:56 PHST- 2022/09/20 00:00 [received] PHST- 2022/11/21 00:00 [accepted] PHST- 2022/12/05 23:56 [entrez] PHST- 2022/12/06 06:00 [pubmed] PHST- 2022/12/15 06:00 [medline] PHST- 2022/12/06 00:00 [pmc-release] AID - 10.1186/s13046-022-02544-6 [pii] AID - 2544 [pii] AID - 10.1186/s13046-022-02544-6 [doi] PST - epublish SO - J Exp Clin Cancer Res. 2022 Dec 6;41(1):335. doi: 10.1186/s13046-022-02544-6.