MicroRNA-7 inhibits the stemness of prostate cancer stem-like cells and tumorigenesis by repressing KLF4/PI3K/Akt/p21 pathway

Oncotarget. 2015 Sep 15;6(27):24017-31. doi: 10.18632/oncotarget.4447.

Abstract

Up to now, the molecular mechanisms underlying the stemness of prostate cancer stem cells (PCSCs) are still poorly understood. In this study, we demonstrated that microRNA-7 (miR-7) appears to be a novel tumor-suppressor miRNA, which abrogates the stemness of PCSCs and inhibits prostate tumorigenesis by suppressing a key stemness factor KLF4. MicroRNA-7 is down-regulated in prostate cancer cells compared to non-tumorigenic prostate epithelial cells. Restoration of miR-7 suppresses the expression of the stemness factor KLF4 in PCSCs and inhibits prostate tumorigenesis both in vitro and in vivo. Interestingly, the suppression of the stemness of PCSCs by miR-7 is sustained for generations in xenografts. Analysis of clinical samples also revealed a negative correlation between miR-7 expression and prostate tumor progression. Mechanistically, overexpression of miR-7 may lead to a cell cycle arrest but not apoptosis, which seems achieved via suppressing the KLF4/PI3K/Akt/p21 pathway. This study identifies miR-7 as a suppressor of PCSCs' stemness and implicates its potential application for PCa therapy.

Keywords: KLF4; PI3K/Akt pathway; cancer stem cells; miR-7; prostate cancer; tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD / metabolism
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Disease Progression
  • Down-Regulation
  • Glycoproteins / metabolism
  • Humans
  • Hyaluronan Receptors / metabolism
  • Kruppel-Like Transcription Factors / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism*
  • Peptides / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Plasmids / metabolism
  • Prostate / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*

Substances

  • AC133 Antigen
  • Antigens, CD
  • CD44 protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • GKLF protein
  • Glycoproteins
  • Hyaluronan Receptors
  • Kruppel-Like Transcription Factors
  • MIRN7 microRNA, human
  • MicroRNAs
  • Peptides
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt