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Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells
被引:32
作者:
Bellazzo, Arianna
[1
]
Di Minin, Giulio
[2
]
Valentino, Elena
[1
,3
]
Sicari, Dania
[1
,3
]
Torre, Denis
[4
]
Marchionni, Luigi
[5
]
Serpi, Federica
[1
]
Stadler, Michael B.
[6
]
Taverna, Daniela
[7
]
Zuccolotto, Gaia
[8
]
Montagner, Isabella Monia
[9
]
Rosato, Antonio
[8
,9
]
Tonon, Federica
[10
]
Zennaro, Cristina
[10
]
Agostinis, Chiara
[11
]
Bulla, Roberta
[3
]
Mano, Miguel
[12
,13
]
Del Sal, Giannino
[1
,3
]
Collavin, Licio
[1
,3
]
机构:
[1] Natl Lab CIB LNCIB, AREA Sci Pk, I-34149 Trieste, Italy
[2] Swiss Fed Inst Technol ETH Honggerberg, Inst Mol Hlth Sci, CH-8093 Zurich, Switzerland
[3] Univ Trieste, Dept Life Sci, I-34127 Trieste, Italy
[4] Icahn Sch Med Mt Sinai, LINCS DCIC BD2K, Mt Sinai Ctr Bioinformat, Dept Pharmacol Sci, New York, NY 10029 USA
[5] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA
[6] Switzerland & Swiss Inst Bioinformat, Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland
[7] Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy
[8] Univ Padua, Dept Surg Oncol & Gastroenterol, I-35128 Padua, Italy
[9] Ist Oncol Veneto IOV IRCCS, I-35128 Padua, Italy
[10] Univ Trieste, Dept Med Surg & Hlth Sci, I-34149 Trieste, Italy
[11] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, I-34137 Trieste, Italy
[12] Univ Coimbra, Ctr Neurosci & Cell Biol CNC, P-3004504 Coimbra, Portugal
[13] ICGEB, I-34149 Trieste, Italy
关键词:
NF-KAPPA-B;
MIGRATION;
PROLIFERATION;
ANGIOGENESIS;
EXPRESSION;
ZEBRAFISH;
PATHWAYS;
INVASION;
COMPLEX;
MODEL;
D O I:
10.1038/s41418-018-0088-5
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and proangiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.
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页码:1224 / 1238
页数:15
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