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Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β–induced Serpine1
- Source :
- Journal of Clinical Investigation. 129:1654-1670
- Publication Year :
- 2019
- Publisher :
- American Society for Clinical Investigation, 2019.
-
Abstract
- In tumors, extravascular fibrin forms provisional scaffolds for endothelial cell (EC) growth and motility during angiogenesis. We report that fibrin-mediated angiogenesis was inhibited and tumor growth delayed following postnatal deletion of Tgfbr2 in the endothelium of Cdh5-Cre(ERT2) Tgfbr2(fl/fl) mice (Tgfbr2(iECKO) mice). ECs from Tgfbr2(iECKO) mice failed to upregulate the fibrinolysis inhibitor plasminogen activator inhibitor 1 (Serpine1, also known as PAI-1), due in part to uncoupled TGF-β–mediated suppression of miR-30c. Bypassing TGF-β signaling with vascular tropic nanoparticles that deliver miR-30c antagomiRs promoted PAI-1–dependent tumor growth and increased fibrin abundance, whereas miR-30c mimics inhibited tumor growth and promoted vascular-directed fibrinolysis in vivo. Using single-cell RNA-Seq and a NanoString miRNA array, we also found that subtypes of ECs in tumors showed spectrums of Serpine1 and miR-30c expression levels, suggesting functional diversity in ECs at the level of individual cells; indeed, fresh EC isolates from lung and mammary tumor models had differential abilities to degrade fibrin and launch new vessel sprouts, a finding that was linked to their inverse expression patterns of miR-30c and Serpine1 (i.e., miR-30c(hi) Serpine1(lo) ECs were poorly angiogenic and miR-30c(lo) Serpine1(hi) ECs were highly angiogenic). Thus, by balancing Serpine1 expression in ECs downstream of TGF-β, miR-30c functions as a tumor suppressor in the tumor microenvironment through its ability to promote fibrin degradation and inhibit blood vessel formation.
- Subjects :
- 0301 basic medicine
Endothelium
Angiogenesis
medicine.medical_treatment
Mice, Transgenic
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Transforming Growth Factor beta
Plasminogen Activator Inhibitor 1
Fibrinolysis
medicine
Animals
RNA, Neoplasm
Mammary tumor
Tumor microenvironment
Neovascularization, Pathologic
Chemistry
Receptor, Transforming Growth Factor-beta Type II
Endothelial Cells
Mammary Neoplasms, Experimental
General Medicine
Neoplasm Proteins
Endothelial stem cell
MicroRNAs
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Plasminogen activator inhibitor-1
Cancer research
Female
Gene Deletion
Research Article
Transforming growth factor
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 129
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....cd2fdc1ea2e2697427433a725016ab89