MEG3-derived miR-493-5p overcomes the oncogenic feature of IGF2-miR-483 loss of imprinting in hepatic cancer cells.

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.

• Authors: Luc Gailhouste, Lee Chuen Liew, Ken Yasukawa, Izuho Hatada, Yasuhito Tanaka, Takashi Kato, Hitoshi Nakagama, Takahiro Ochiya
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 8 Pg. 553 (07 18 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 31320614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IGF2 protein, human
• MEG3 non-coding RNA, human
• MIRN483 microRNA, human
• MIRN493 microRNA, human
• MicroRNAs
• RNA, Long Noncoding
• Insulin-Like Growth Factor II

Topics

• Animals
• Carcinoma, Hepatocellular (genetics, metabolism, 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, metabolism)
• Introns
• Liver Neoplasms (genetics, metabolism, pathology)
• Mice
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• RNA, Long Noncoding (genetics, metabolism)
• Transplantation, Heterologous