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Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2018 Jul; Vol. 25 (7), pp. 1224-1238. Date of Electronic Publication: 2018 Mar 22. - Publication Year :
- 2018
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Abstract
- 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 pro-angiogenic 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.
- Subjects :
- Animals
HCT116 Cells
HeLa Cells
Hep G2 Cells
Human Umbilical Vein Endothelial Cells
Humans
Male
MicroRNAs genetics
Neoplasm Proteins genetics
PC-3 Cells
Prostatic Neoplasms genetics
Prostatic Neoplasms pathology
RNA, Neoplasm genetics
Zebrafish
ras GTPase-Activating Proteins genetics
MicroRNAs metabolism
Neoplasm Proteins metabolism
Prostatic Neoplasms metabolism
RNA, Neoplasm metabolism
Signal Transduction
Tumor Microenvironment
ras GTPase-Activating Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5403
- Volume :
- 25
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 29568059
- Full Text :
- https://doi.org/10.1038/s41418-018-0088-5