Reprogramming Using microRNA-302 Improves Drug Sensitivity in Hepatocellular Carcinoma Cells

Chikato Koga, Shogo Kobayashi, Hiroaki Nagano, Yoshito Tomimaru, Naoki Hama, Hiroshi Wada, Koichi Kawamoto, Hidetoshi Eguchi, Masamitsu Konno, Hideshi Ishii, Koji Umeshita, Yuichiro Doki, Masaki Mori

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Background: Although studies have shown that Oct4, Sox2, Klf4, and c-Myc (OKSM)-mediated induced pluripotent stem cell (iPSC) technology sensitizes cancer cells to drugs, the potential risk of inserting c-Myc and random insertions of exogenous sequences into the genome persists. Several authors, including us, have presented microRNA (miRNA)-mediated reprogramming as an alternative approach. Herein, we evaluated the efficacy of miRNA-mediated reprogramming on hepatocellular carcinoma (HCC) cells.

Conclusions: miR-302–mediated iPSC technology reprogrammed HCC cells and improved drug sensitivity through AOF2 down-regulation, which caused H3K4 methylation and c-Myc repression.

Methods: Among three miRNAs (miR-200c, miR-302s, and miR-369s) that were previously presented for miRNA-mediated reprogramming, miR-302 was expressed at low levels in HCC cells. After transfecting three times with miR-302, the cells were incubated in ES medium for 3 weeks and then characterized.

Results: iPSC-like spheres were obtained after the 3-week incubation. Spheres presented high NANOG and OCT4 expression, low proliferation, high apoptosis, low epithelial-mesenchymal transition marker expression (N-cadherin, TGFBR2), and sensitization to drugs. Several miRNAs were changed (e.g., low oncomiR miR-21, high miR-29b). cMyc was decreased, and methylation was elevated on histone 3 at lysine 4 (H3K4). Differentiated cells expressed markers of each germ layer (GFAP, FABP4, and ALB). AOF2 (also known as LSD1 or KDM1), one of the targets for miR-302, was repressed in iPSC-like-spheres. Silencing of AOF2 resulted in similar features of iPSC-like-spheres, including cMyc down-regulation and H3K4 methylation. In drug-resistant cells, sensitization was achieved through miR-302-mediated reprogramming.

Original languageEnglish
Pages (from-to)591-600
Number of pages10
JournalAnnals of Surgical Oncology
Volume21
Issue number4
DOIs
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Surgery
  • Oncology

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