title: 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.affiliation: Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, DAHFMO, Unit of Histology and Medical Embryology, Istituto Pasteur-Fondazione Cenci Bolognetti, La Sapienza University of Rome, 00161 Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Galli
authors.forename: Alessio
authors.initials: A
authors.lastname: Paone
authors.forename: Muller
authors.initials: M
authors.lastname: Fabbri
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.forename: Federica
authors.initials: F
authors.lastname: Calore
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.forename: Mario
authors.initials: M
authors.lastname: Acunzo
authors.forename: Antonella
authors.initials: A
authors.lastname: Stoppacciaro
authors.forename: Andrea
authors.initials: A
authors.lastname: Tubaro
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.forename: Paolo
authors.initials: P
authors.lastname: Fadda
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Antonio
authors.initials: A
authors.lastname: Filippini
authors.forename: Elio
authors.initials: E
authors.lastname: Ziparo
authors.forename: Anna
authors.initials: A
authors.lastname: Riccioli
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C550570:MIRN148 microRNA, human; C550856:MIRN152 microRNA, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D018168:Receptors, Retinoic Acid; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C082925:retinoic acid receptor beta; D014212:Tretinoin; D004248:DNA (Cytosine-5-)-Methyltransferases; D011070:Poly I-C
keywords: combined chemotherapy; inflammation