miR-148a-3p represses proliferation and EMT by establishing regulatory circuits between ERBB3/AKT2/c-myc and DNMT1 in bladder cancer

Cell Death Dis. 2016 Dec 1;7(12):e2503. doi: 10.1038/cddis.2016.373.

Abstract

miR-148a-3p downregulation has emerged as a critical factor in cancer progression yet, the underlying mechanisms of miR-148a-3p expression pattern and its function in bladder cancer remains to be elucidated. Here, we illustrate that miR-148a-3p is frequently downregulated in bladder cancer and that its expression may be regulated by DNA methylation. DNA methyltransferase 1 (DNMT1) and miR-148a-3p function in a positive feedback loop in bladder cancer. miR-148a-3p overexpression functions as a tumor suppressor in bladder cancer cells. miR-148a-3p inhibits bladder cancer cell proliferation and epithelial-mesenchymal transition (EMT) by regulating ERBB3/AKT2/c-myc and ERBB3/AKT2/Snail signaling. ERBB3, DNMT1 and AKT2 are downstream miR-148a-3p target genes. Furthermore, the miR-148a-3p/ERBB3/AKT2/c-myc signaling axis establishes a positive feedback loop in the regulation of bladder cancer. Taken together, our study demonstrates novel regulatory circuits involving miR-148a-3p/ERBB3/AKT2/c-myc and DNMT1 that controls bladder cancer progression, which may be useful in the development of more effective therapies against bladder cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Base Sequence
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation / genetics
  • Down-Regulation / genetics
  • Epithelial-Mesenchymal Transition / genetics*
  • Feedback, Physiological
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Biological
  • Multivariate Analysis
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA, Small Interfering / metabolism
  • Receptor, ErbB-3 / metabolism*
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology*

Substances

  • MIRN148 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • DNA (Cytosine-5-)-Methyltransferases
  • ERBB3 protein, human
  • Receptor, ErbB-3
  • Proto-Oncogene Proteins c-akt