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

被引：57

作者：

Galli, Roberta ^{[1
,2
,3
]}

Paone, Alessio ^{[2
,3
]}

Fabbri, Muller ^{[4
,5
,6
,7
]}

Zanesi, Nicola ^{[2
,3
]}

Calore, Federica ^{[2
,3
]}

Cascione, Luciano ^{[2
,3
,8
]}

Acunzo, Mario ^{[2
,3
]}

Stoppacciaro, Antonella ^{[9
]}

Tubaro, Andrea ^{[9
]}

Lovat, Francesca ^{[2
,3
]}

Gasparini, Pierluigi ^{[2
,3
]}

Fadda, Paolo ^{[2
,3
]}

Alder, Hansjuerg ^{[2
,3
]}

Volinia, Stefano ^{[2
,3
,10
]}

Filippini, Antonio ^{[1
]}

Ziparo, Elio ^{[1
]}

Riccioli, Anna ^{[1
]}

Croce, Carlo M. ^{[2
,3
]}

机构：

[1] Univ Roma La Sapienza, Unit Histol & Med Embryol, Dept Anat Histol Forens & Orthopaed Sci DAHFMO, Ist Pasteur,Fdn Cenci Bolognetti, I-00161 Rome, Italy

[2] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA

[3] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA

[4] Univ So Calif, Childrens Ctr Canc & Blood Dis, Los Angeles, CA 90089 USA

[5] Univ So Calif, Dept Mol Microbiol & Immunol, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA

[6] Univ So Calif, Keck Sch Med, Los Angeles, CA 90089 USA

[7] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA

[8] Univ Catania, Dept Clin & Mol Biomed, I-95122 Catania, Italy

[9] Univ Roma La Sapienza, Osped St Andrea, Dept Clin & Mol Med, I-00185 Rome, Italy

[10] Univ Ferrara, Dept Morphol & Embryol, I-44100 Ferrara, Italy

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 24期

基金：

美国国家卫生研究院;

关键词：

inflammation; combined chemotherapy; GENE-EXPRESSION; PROSTATE-CANCER; CELLS; METHYLATION; BREAST; STIMULATION; APOPTOSIS; PROMOTER; IMMUNITY;

D O I：

10.1073/pnas.1304610110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：9812 / 9817

页数：6

共 31 条

[1] RETINOIC ACID RECEPTORS AND RETINOID X-RECEPTORS - INTERACTIONS WITH ENDOGENOUS RETINOIC ACIDS [J].