miR-203 inhibits proliferation and self-renewal of leukemia stem cells by targeting survivin and Bmi-1

Sci Rep. 2016 Feb 5:6:19995. doi: 10.1038/srep19995.

Abstract

Drug resistance is one of the leading causes of failed cancer therapy in the treatment of acute myeloid leukemia. Although the mechanisms of resistance are poorly understood, they may be related to the presence of leukemia stem cells (LSCs). Down-regulation of the miR-203 reportedly contributes to oncogenesis and chemo-resistance in multiple cancers. We found that miR-203 expression was down-regulated in CD34 + AML cells as compared with CD34- cells isolated from patients as well as in LSC-enriched (CD34 + CD38-) cell lines KG-1a or MOLM13. Additionally, re-expression of miR-203 led to decreased cell proliferation, self-renewal, and sphere formation in LSCs. Moreover, miR-203 was found to directly target the 3'un-translated regions of survivin and Bmi-1 mRNAs affecting proliferation and self-renewal in LSCs. In this study, we identified a novel miR-203/survivin/Bmi-1 axis involved in the regulation of biological properties of LSCs. This axis may represent a new therapeutic target for acute myeloid leukemia and a potential prognosis/diagnostic marker for LSCs therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Antigens, CD34 / metabolism
  • Base Sequence
  • Cell Line, Tumor
  • Cell Proliferation
  • Down-Regulation
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Leukemia, Myeloid, Acute / therapy
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • MicroRNAs / therapeutic use
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism*
  • Polycomb Repressive Complex 1 / antagonists & inhibitors
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / metabolism*
  • RNA Interference
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Real-Time Polymerase Chain Reaction
  • Sequence Alignment
  • Survivin

Substances

  • 3' Untranslated Regions
  • Antigens, CD34
  • BIRC5 protein, human
  • BMI1 protein, human
  • Inhibitor of Apoptosis Proteins
  • MIRN203 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • RNA, Small Interfering
  • Survivin
  • Polycomb Repressive Complex 1