miR181b is induced by the chemopreventive polyphenol curcumin and inhibits breast cancer metastasis via down-regulation of the inflammatory cytokines CXCL1 and -2.
Chronic inflammation is a major risk factor for the development and metastatic progression of cancer. We have previously reported that the chemopreventive polyphenol Curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast and prostate cancer metastases. In the present study, we have analyzed the effects of Curcumin on miRNA expression and its correlation to the anti-tumorigenic properties of this natural occurring polyphenol. Using microarray miRNA expression analyses, we show here that Curcumin modulates the expression of a series of miRNAs, including miR181b, in metastatic breast cancer cells. Interestingly, we found that miR181b down-modulates CXCL1 and -2 through a direct binding to their 3'-UTR. Overexpression or inhibition of miR181b in metastatic breast cancer cells has a significant impact on CXCL1 and -2 and is required for the effect of Curcumin on these two cytokines. miR181b also mediates the effects of Curcumin on inhibition of proliferation and invasion as well as induction of apoptosis. Importantly, over-expression of miR181b in metastatic breast cancer cells inhibits metastasis formation in vivo in immunodeficient mice. Finally, we demonstrated that Curcumin up-regulates miR181b and down-regulates CXCL1 and -2 in cells isolated from several primary human breast cancers. Taken together, these data show that Curcumin provides a simple bridge to bring metastamir modulation into the clinic, placing it in a primary and tertiary preventive, as well as a therapeutic, setting.
Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany.
Emanuel
E
Kronski
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Micol E
ME
Fiori
Department of Experimental Medicine, University of Genoa, Genoa, Italy; Embryogenesis and Tumorigenesis in Animal Models, IRCCS AOU San Martino-IST National Cancer Research Institute, Genoa, Italy.
Ottavia
O
Barbieri
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Simonetta
S
Astigiano
Integrated Molecular Pathology, IRCCS AOU San Martino-IST National Cancer Research Institute, Genoa, Italy.
Valentina
V
Mirisola
Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany.
Peter H
PH
Killian
Scientific and Technologic Pole, Fondazione Onlus MultiMedica, Milan, Italy.
Antonino
A
Bruno
Scientific and Technologic Pole, Fondazione Onlus MultiMedica, Milan, Italy.
Arianna
A
Pagani
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
Francesca
F
Rovera
Integrated Molecular Pathology, IRCCS AOU San Martino-IST National Cancer Research Institute, Genoa, Italy.
Ulrich
U
Pfeffer
Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany.
Christian P
CP
Sommerhoff
Scientific and Technologic Pole, Fondazione Onlus MultiMedica, Milan, Italy; Department of Biotechnologies and Life Sciences, University of Insubria, Varese, Italy.
Douglas M
DM
Noonan
Institute of Pathology, Academic Hospital Munich-Bogenhausen, Munich, Germany.
Andreas G
AG
Nerlich
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Laura
L
Fontana
Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany. Electronic address: bachmeier.beatrice@gmail.com.
Beatrice E
BE
Bachmeier
D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000235:genetics*; D054426:Chemokine CXCL2 / Q000235:genetics*; D003474:Curcumin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D003474:Curcumin
Breast cancer; Curcumin; Inflammatory cytokines; Metastases prevention; microRNAs