MiR-34a and miR-34b/c have distinct effects on the suppression of lung adenocarcinomas

Exp Mol Med. 2019 Jan 17;51(1):1-10. doi: 10.1038/s12276-018-0203-1.

Abstract

Three miR-34 family members (miR-34a, miR-34b, and miR-34c) are clustered on two different chromosomal loci, Mir34a and Mir34b/c. These miRNAs have identical seed sequences, which are predicted to target the same set of genes. However, miR-34a and miR-34c have different sets of negatively correlated genes in lung adenocarcinoma data from The Cancer Genome Atlas. Therefore, we hypothesized that the individual miR-34 family members, which are tumor suppressive miRNAs, would have varying effects on lung tumorigenesis. To show this, we overexpressed each miR-34 cluster in murine lung cancer cells. MiR-34b/c enhanced cancer cell attachment and suppressed cell growth and invasion compared with miR-34a. In a syngeneic mouse model, both miR-34a and miR-34b/c blocked lung metastasis. However, miR-34b/c suppressed tumor growth more than miR-34a. MiR-34b/c also decreased the expression of mesenchymal markers (Cdh2 and Fn1) and increased the expression of epithelial markers (Cldn3, Dsp, and miR-200) to a greater degree than miR-34a. These results imply that miR-34b and miR-34c inhibit epithelial-to-mesenchymal transition. Furthermore, knockout of all three miR-34 members promoted mutant Kras-driven lung tumor progression in mice. Similarly, lung adenocarcinoma patients with higher miR-34a/b/c levels had better survival rates than did those with lower levels. In summary, we suggest that miR-34b and miR-34c are more effective tumor suppressors than miR-34a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Claudin-3 / genetics
  • Claudin-3 / metabolism
  • Desmoplakins / genetics
  • Desmoplakins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neoplasm Metastasis

Substances

  • Cadherins
  • Cdh2 protein, mouse
  • Claudin-3
  • Cldn3 protein, mouse
  • Desmoplakins
  • Dsp protein, mouse
  • MIRN34a microRNA, mouse
  • MicroRNAs
  • Mirn200 microRNA, mouse