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

Roberta Galli (1) , Alessio Paone (2) , Muller Fabbri (3, 4) , Nicola Zanesi (2) , Federica Calore (2) , Luciano Cascione (5, 2) , Mario Acunzo (2) , Antonella Stoppacciaro (6) , Andrea Tubaro (6) , Francesca Lovat (2) , Pierluigi Gasparini (2) , Paolo Fadda (2) , Hansjuerg Alder (2) , Stefano Volinia (2) , Antonio Filippini (1) , Elio Ziparo (1) , Anna Riccioli (1) , Carlo M Croce (2)

1 DAHFMO - Department of Anatomy, Histology, Forensic Medicine and Orthopedic [Roma]
2 Comprehensive Cancer Center [Colombus]
3 Keck School of Medicine [Los Angeles]
4 Saban Research Institute of Children’s Hospital Los Angeles
5 Department of Clinical and Molecular Medicine
6 Department of Clinical and Molecular Medicine

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.

Domaines: Cancer

Roberta Galli, Alessio Paone, Muller Fabbri, Nicola Zanesi, Federica Calore, et al.. Toll-like receptor 3 (TLR3) activation induces microRNA-dependent reexpression of functional RARβ and tumor regression.. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110 (24), pp.9812-7. ⟨10.1073/pnas.1304610110⟩. ⟨pasteur-01026265⟩