RRC ID 57870
Author Gailhouste L, Liew LC, Yasukawa K, Hatada I, Tanaka Y, Kato T, Nakagama H, Ochiya T.
Title MEG3-derived miR-493-5p overcomes the oncogenic feature of IGF2-miR-483 loss of imprinting in hepatic cancer cells.
Journal Cell Death Dis
Abstract Numerous studies have described the critical role played by microRNAs (miRNAs) in cancer progression and the potential of these small non-coding RNAs for diagnostic or therapeutic applications. However, the mechanisms responsible for the altered expression of miRNAs in malignant cells remain poorly understood. Herein, via epigenetic unmasking, we identified a group of miRNAs located in the imprinted delta like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3 (MEG3) locus that were repressed in hepatic tumor cells. Notably, miR-493-5p epigenetic silencing was correlated with hypermethylation of the MEG3 differentially regulated region (DMR) in liver cancer cell lines and tumor tissues from patients. Experimental rescue of miR-493-5p promoted an anti-cancer response by hindering hepatocellular carcinoma (HCC) cell growth in vitro and tumor progression in vivo. We found that miR-493-5p mediated part of its tumor-suppressor activity by abrogating overexpression of insulin-like growth factor 2 (IGF2) and the IGF2-derived intronic oncomir miR-483-3p in HCC cells characterized by IGF2 loss of imprinting (LOI). In summary, this study describes an unknown miRNA-dependent regulatory mechanism between two distinct imprinted loci and a possible therapeutic window for liver cancer patients exhibiting IGF2-miR-483 LOI and amplification.
Volume 10(8)
Pages 553
Published 2019-7-18
DOI 10.1038/s41419-019-1788-6
PII 10.1038/s41419-019-1788-6
PMID 31320614
PMC PMC6639415
MeSH Animals Carcinoma, Hepatocellular / genetics* Carcinoma, Hepatocellular / metabolism Carcinoma, Hepatocellular / pathology Cell Line, Tumor Cell Movement / genetics Cell Survival / genetics DNA Methylation Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic / genetics Genes, Tumor Suppressor Genomic Imprinting / genetics* Humans Insulin-Like Growth Factor II / genetics* Insulin-Like Growth Factor II / metabolism Introns Liver Neoplasms / genetics* Liver Neoplasms / metabolism Liver Neoplasms / pathology Mice Mice, Nude MicroRNAs / genetics MicroRNAs / metabolism* RNA, Long Noncoding / genetics RNA, Long Noncoding / metabolism* Transplantation, Heterologous
IF 6.304
Times Cited 9
Human and Animal Cells Hep G2