The therapeutic effect of miR-125b is enhanced by the prostaglandin endoperoxide synthase 2/cyclooxygenase 2 blockade and hampers ETS1 in the context of the microenvironment of bone metastasis

Cell Death Dis. 2018 May 1;9(5):472. doi: 10.1038/s41419-018-0499-8.

Abstract

Bone is the most common site for breast cancer spread. In the pro-metastatic cell line 1833, derived from MDA-MB-231 breast adenocarcinoma cells, both hypoxia and hepatocyte growth factor (HGF) influence the effect of miR-125b on ETS proto-oncogene 1 transcription factor (ETS1). The effect of hypoxia inducible factor 1 alpha subunit (HIF1A), known to promote metastatic spread by upregulating prostaglandin endoperoxide synthase 2 (PTGS2), may be dampened by miR-125b targeting PTGS2. Here, we investigated whether miR-125b plays a role in breast cancer metastasis by measuring its activity in response to the chemotherapeutic agent NS-398 in a xenograft model. NS-398 is typically used in the clinic to target PTGS2. We also aimed to describe the molecular mechanisms in vitro, since the enhancement of epithelial properties may favor the efficacy of therapies. We report that in the xenograft model, miR-125b reduced metastasis to the bone. We also report suppression of PTGS2 enhanced survival by decreasing HIF1A in cells within the bone marrow. In 1833 cells transfected with a miR-125b mimic we observed several phenotypic changes including enhancement of the epithelial marker E-cadherin, a reduction of mesenchymal-associated genes and a reduction of WNT-associated stem cell signaling. Our findings suggest that in vivo, key players of the bone microenvironment promoting breast cancer spread are regulated by miR-125b. In future, biological molecules imitating miR-125b may enhance the sensitivity of chemotherapeutic agents used to counteract bone metastases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Animals
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / secondary
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Metastasis
  • Nitrobenzenes / pharmacology*
  • Proto-Oncogene Mas
  • Proto-Oncogene Protein c-ets-1 / genetics
  • Proto-Oncogene Protein c-ets-1 / metabolism*
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*
  • Sulfonamides / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • ETS1 protein, human
  • MAS1 protein, human
  • MIRN125 microRNA, human
  • MicroRNAs
  • Nitrobenzenes
  • Proto-Oncogene Mas
  • Proto-Oncogene Protein c-ets-1
  • RNA, Neoplasm
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Cyclooxygenase 2
  • PTGS2 protein, human