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

Luc Gailhouste, Lee Chuen Liew, Ken Yasukawa, Izuho Hatada, Yasuhito Tanaka, Takashi Kato, Hitoshi Nakagama, Takahiro Ochiya

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number553
JournalCell Death and Disease
Volume10
Issue number8
DOIs
Publication statusPublished - 2019 Aug 1

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Somatomedins
Liver Neoplasms
Hepatocytes
MicroRNAs
Neoplasms
Epigenomics
Hepatocellular Carcinoma
Small Untranslated RNA
Tumor Cell Line
Ligands
Therapeutics
Growth

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

MEG3-derived miR-493-5p overcomes the oncogenic feature of IGF2-miR-483 loss of imprinting in hepatic cancer cells. / Gailhouste, Luc; Liew, Lee Chuen; Yasukawa, Ken; Hatada, Izuho; Tanaka, Yasuhito; Kato, Takashi; Nakagama, Hitoshi; Ochiya, Takahiro.

In: Cell Death and Disease, Vol. 10, No. 8, 553, 01.08.2019.

Research output: Contribution to journalArticle

Gailhouste, Luc ; Liew, Lee Chuen ; Yasukawa, Ken ; Hatada, Izuho ; Tanaka, Yasuhito ; Kato, Takashi ; Nakagama, Hitoshi ; Ochiya, Takahiro. / MEG3-derived miR-493-5p overcomes the oncogenic feature of IGF2-miR-483 loss of imprinting in hepatic cancer cells. In: Cell Death and Disease. 2019 ; Vol. 10, No. 8.
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