miR-101 inhibits cholangiocarcinoma angiogenesis through targeting vascular endothelial growth factor (VEGF)

Am J Pathol. 2013 May;182(5):1629-39. doi: 10.1016/j.ajpath.2013.01.045.


Recent evidence has suggested an important role of miRNAs in liver biology and diseases, although the implication of miRNAs in cholangiocarcinoma remains to be defined further. This study was designed to examine the biological function and molecular mechanism of miR-101 in cholangiocarcinogenesis and tumor progression. In situ hybridization and quantitative RT-PCR were performed to determine the expression of miR-101 in human cholangiocarcinoma tissues and cell lines. Compared with noncancerous biliary epithelial cells, the expression of miR-101 is decreased in 43.5% of human cholangiocarcinoma specimens and in all three cholangiocarcinoma cell lines used in this study. Forced overexpression of miR-101 significantly inhibited cholangiocarcinoma growth in severe combined immunodeficiency mice. miR-101-overexpressed xenograft tumor tissues showed decreased capillary densities and decreased levels of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). The VEGF and COX-2 mRNAs were identified as the bona fide targets of miR-101 in cholangiocarcinoma cells by both computational analysis and experimental assays. miR-101 inhibits cholangiocarcinoma angiogenesis by direct targeting of VEGF mRNA 3'untranslated region and by repression of VEGF gene transcription through inhibition of COX-2. This study established a novel tumor-suppressor role of miR-101 in cholangiocarcinoma and it suggests the possibility of targeting miR-101 and related signaling pathways for future therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cholangiocarcinoma / blood supply*
  • Cholangiocarcinoma / genetics*
  • Cholangiocarcinoma / pathology
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / pathology*
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Transcription, Genetic / drug effects
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*


  • MIRN101 microRNA, human
  • MicroRNAs
  • Vascular Endothelial Growth Factor A
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Dinoprostone