Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development

Cancer Discov. 2016 Feb;6(2):188-201. doi: 10.1158/2159-8290.CD-15-0854. Epub 2015 Nov 19.

Abstract

The two unrelated miRNAs miR-143 and miR-145, coexpressed from the miR-143/145 cluster, have been proposed to act as tumor suppressors in human cancer, and therapeutic benefits of delivering miR-143 and miR-145 to tumors have been reported. In contrast, we found that tumor-specific deletion of miR-143/145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. This was consistent with the lack of endogenous miR-143/145 expression in normal and transformed lung epithelium. Surprisingly, miR-143/145 in the tumor microenvironment dramatically promoted tumor growth by stimulating the proliferation of endothelial cells. Loss of miR-143/145 in vivo led to derepression of the miR-145 target CAMK1D, an inhibitory kinase, which when overexpressed prevents mitotic entry of endothelial cells. As a consequence, tumors in miR-143/145-deficient animals exhibited diminished neoangiogenesis, increased apoptosis, and their expansion was limited by the tumor's ability to co-opt the alveolar vasculature. These findings demonstrate that stromal miR-143/145 promotes tumorigenesis and caution against the use of these miRNAs as agents in cancer therapeutics.

Significance: This study shows that miR-143/145 expressed from the tumor microenvironment stimulates neoangiogenesis and supports tumor expansion in the lung, demonstrating a surprising role for the putative tumor suppressor miRNA cluster in promoting tumorigenesis. We propose inhibition of miR-143/145 as a therapeutic avenue to modulate tumor neoangiogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1 / metabolism
  • Cell Differentiation
  • Cell Line, Tumor
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neoplasms, Experimental
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Stromal Cells / cytology
  • Stromal Cells / metabolism
  • Tumor Microenvironment

Substances

  • MIRN145a microRNA, mouse
  • MicroRNAs
  • MIRN143 microRNA, mouse
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1
  • Camk1d protein, mouse