The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis

Sci Rep. 2013;3:2392. doi: 10.1038/srep02392.

Abstract

The brain microenvironment promotes metastasis through mechanisms that remain elusive. Co-culture of lung cancer cells with astrocytes - the most abundant cell type within the metastatic brain niche - lead to downregulation of miRNA-768-3p which drives K-ras expression and key signaling pathways, enhances cell viability and promotes chemotherapeutic resistance. Vector-based forced expression of miRNA-768-3p complementary sequence or a chemically-engineered miRNA-768-3p inhibitor recapitulated the astrocyte effect to increase tumor cell viability. The miRNA-768-3p inhibitor targeted the K-ras 3'-UTR as demonstrated by increased luminescence from a luciferase reporter and strikingly increased the K-ras protein and the downstream effectors ERK1/2 and B-Raf. miRNA-768-3p was reduced in patient brain metastases compared to normal brain tissue and was lower in patient tissue from brain metastases compared to same-patient primary tumour tissue. The brain microenvironment negatively regulates miRNA-768-3p to enhance K-ras and promote metastasis. We propose that therapeutic replacement of the metastasis suppressor miRNA-768-3p holds clinical promise.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Survival
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins p21(ras)
  • RNA, Messenger / metabolism*
  • Signal Transduction
  • Tumor Microenvironment / physiology*
  • ras Proteins / metabolism*

Substances

  • KRAS protein, human
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins