Toll-like receptor 3 (TLR3) activation induces microRNA-dependent reexpression of functional RARβ and tumor regression

Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9812-7. doi: 10.1073/pnas.1304610110. Epub 2013 May 28.

Abstract

Toll-like receptor 3 (TLR3) is a key effector of the innate immune system against viruses. Activation of TLR3 exerts an antitumoral effect through a mechanism of action still poorly understood. Here we show that TLR3 activation by polyinosinic:polycytidylic acid induces up-regulation of microRNA-29b, -29c, -148b, and -152 in tumor-derived cell lines and primary tumors. In turn, these microRNAs induce reexpression of epigenetically silenced genes by targeting DNA methyltransferases. In DU145 and TRAMP-C1 prostate and MDA-MB-231 breast cancer cells, we demonstrated that polyinosinic:polycytidylic acid-mediated activation of TLR3 induces microRNAs targeting DNA methyltransferases, leading to demethylation and reexpression of the oncosuppressor retinoic acid receptor beta (RARβ). As a result, cancer cells become sensitive to retinoic acid and undergo apoptosis both in vitro and in vivo. This study provides evidence of an antitumoral mechanism of action upon TLR3 activation and the biological rationale for a combined TLR3 agonist/retinoic acid treatment of prostate and breast cancer.

Keywords: combined chemotherapy; inflammation.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Immunoblotting
  • Male
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics*
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Poly I-C / pharmacology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / prevention & control
  • Receptors, Retinoic Acid / genetics*
  • Receptors, Retinoic Acid / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 3 / agonists
  • Toll-Like Receptor 3 / genetics*
  • Toll-Like Receptor 3 / metabolism
  • Tretinoin / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • MIRN148 microRNA, human
  • MIRN152 microRNA, human
  • MIRN29a microRNA, human
  • MicroRNAs
  • Receptors, Retinoic Acid
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • retinoic acid receptor beta
  • Tretinoin
  • DNA (Cytosine-5-)-Methyltransferases
  • Poly I-C