PMID- 30971290 OWN - NLM STAT- MEDLINE DCOM- 20190819 LR - 20231213 IS - 1756-9966 (Electronic) IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 38 IP - 1 DP - 2019 Apr 10 TI - Long noncoding RNA EPB41L4A-AS2 inhibits hepatocellular carcinoma development by sponging miR-301a-5p and targeting FOXL1. PG - 153 LID - 10.1186/s13046-019-1128-9 [doi] LID - 153 AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the major histological type of liver cancer with high morbidity and mortality worldwide. Long noncoding RNAs (lncRNA) has been proved to be associated with various cancer types, while its regulation in HCC is largely unknown. METHODS: To figure out the specific role of lncRNA EPB41L4A-AS2 in HCC. Fluorescence in situ hybridization (FISH) was first used to determine the cellular sublocalization of EPB41L4A-AS2 to determine its primary mode of action. QRT-PCR, Western blot and hematoxylin-eosin staining were then used to measure the expression of genes in cells and tissues. Cell proliferation and invasion assays were performed to determine the effects of EPB41L4A-AS2, miR-301a-5p and FOXL1 on the malignant phenotype of tumor cells. With luciferase reporter assay, the direct interaction between target genes were further confirmed for research on molecular mechanism. Finally, the mice hepatocarcinoma model was also established to disclose the tumor suppressor effects of EPB41L4A-AS2 in vivo. RESULTS: Here, we have identified a novel lncRNA EPB41L4A-AS2, which is significantly downregulated both in HCC cells and tissues, and plays a negative regulatory role in HCC proliferation and invasion. Mechanistically, cytoplasmic lncRNA EPB41L4A-AS2 functions as an efficient miR-301a-5p sponge, thereby release the expression inhibition of forkhead box L1 (FOXL1). Indeed, lncRNA EPB41L4A-AS2 inhibits proliferation and migration by upregulating FOXL1 expression and FOXL1 was confirmed as a direct target of miR-301a-5p. MiR-301a-5p shows an inverse correlation with EPB41L4A-AS2 expression and was verified as a direct target of EPB41L4A-AS2 as well. Correspondingly, FOXL1 and miR-301a-5p show opposite biological effects in cell proliferation and migration. Moreover, miR-301a-5p overexpression rescued the EPB41L4A-AS2 upregulation induced depression in proliferation, migration and invasion of HCC cells, as well as promotion effect on FOXL1 expression. Also, in vivo experiments proved that EPB41L4A-AS2 suppress tumor growth and extrahepatic metastasis (lung) via the miR-301a-5p-FOXL1 axis. CONCLUSIONS: Taken together, this research revealed a concrete mechanism of lncRNA EPB41L4A-AS2 in HCC, which may serve as a potential biomarkers and novel therapeutic targets for further clinical application. FAU - Wang, Yu-Gang AU - Wang YG AD - Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Wang, Tao AU - Wang T AD - Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. FAU - Shi, Min AU - Shi M AD - Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. SM1790@shtrhospital.com. FAU - Zhai, Bo AU - Zhai B AD - Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. zhaiboshi@sina.com. LA - eng PT - Journal Article DEP - 20190410 PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - 0 (FOXL1 protein, human) RN - 0 (Forkhead Transcription Factors) RN - 0 (Foxl1 protein, mouse) RN - 0 (MIRN301A microRNA, human) RN - 0 (MIRN301 microRNA, mouse) RN - 0 (MicroRNAs) RN - 0 (RNA, Long Noncoding) MH - Animals MH - Carcinoma, Hepatocellular/*genetics/metabolism/pathology MH - Cell Line, Tumor MH - Cell Proliferation/physiology MH - Forkhead Transcription Factors/genetics/*metabolism MH - Humans MH - Liver Neoplasms/*genetics/metabolism/pathology MH - Liver Neoplasms, Experimental/genetics/metabolism/pathology MH - Mice MH - MicroRNAs/genetics/*metabolism MH - RNA, Long Noncoding/genetics/*metabolism PMC - PMC6458726 OTO - NOTNLM OT - EPB41L4A-AS2 OT - FOXL1 OT - Hepatocellular carcinoma OT - Noncoding RNA OT - miR-301a-5p COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: This study was approved by the ethics committee of Shanghai Tongren Hospital and written consents were obtained from all patients involved. CONSENT FOR PUBLICATION: All the authors have read the manuscript and agreed with the evidence and conclusions in it. We confirm that this paper has not been published previously and if acceptable, will not be published elsewhere. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/04/12 06:00 MHDA- 2019/08/20 06:00 PMCR- 2019/04/10 CRDT- 2019/04/12 06:00 PHST- 2018/09/27 00:00 [received] PHST- 2019/03/05 00:00 [accepted] PHST- 2019/04/12 06:00 [entrez] PHST- 2019/04/12 06:00 [pubmed] PHST- 2019/08/20 06:00 [medline] PHST- 2019/04/10 00:00 [pmc-release] AID - 10.1186/s13046-019-1128-9 [pii] AID - 1128 [pii] AID - 10.1186/s13046-019-1128-9 [doi] PST - epublish SO - J Exp Clin Cancer Res. 2019 Apr 10;38(1):153. doi: 10.1186/s13046-019-1128-9.