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

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.

• Authors: Roberta Galli, Alessio Paone, Muller Fabbri, Nicola Zanesi, Federica Calore, Luciano Cascione, Mario Acunzo, Antonella Stoppacciaro, Andrea Tubaro, Francesca Lovat, Pierluigi Gasparini, Paolo Fadda, Hansjuerg Alder, Stefano Volinia, Antonio Filippini, Elio Ziparo, Anna Riccioli, Carlo M Croce
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 24 Pg. 9812-7 (Jun 11 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23716670 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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