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

作者：Galli Roberta; Paone Alessio; Fabbri Muller; Zanesi Nicola; Calore Federica; Cascione Luciano; Acunzo Mario; Stoppacciaro Antonella; Tubaro Andrea; Lovat Francesca; Gasparini Pierluigi; Fadda Paolo; Alder Hansjuerg; Volinia Stefano; Filippini Antonio; Ziparo Elio; Riccioli Anna; Croce Carlo M^*

来源：Proceedings of the National Academy of Sciences, 2013, 110(24): 9812-9817.

DOI：10.1073/pnas.1304610110

• inflammation
• combined chemotherapy

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 (RAR beta). 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.

• 出版日期2013-6-11