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Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β-induced Serpine1.

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-CreERT2 Tgfbr2fl/fl mice (Tgfbr2iECKO mice). ECs from Tgfbr2iECKO 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-30chi Serpine1lo ECs were poorly angiogenic and miR-30clo Serpine1hi 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.

SUBMITTER: McCann JV

PROVIDER: S-EPMC6436861 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β-induced Serpine1.

McCann James V JV Xiao Lin L Kim Dae Joong DJ Khan Omar F OF Kowalski Piotr S PS Anderson Daniel G DG Pecot Chad V CV Azam Salma H SH Parker Joel S JS Tsai Yihsuan S YS Wolberg Alisa S AS Turner Stephen D SD Tatsumi Kohei K Mackman Nigel N Dudley Andrew C AC

The Journal of clinical investigation 20190311 4

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-CreERT2 Tgfbr2fl/fl mice (Tgfbr2iECKO mice). ECs from Tgfbr2iECKO mice failed to upregulate the fibrinolysis inhibitor plasminogen activator inhibitor 1 (Serpine1, also known as PAI-1), due in part to uncoupled TGF-β-mediate ...[more]

PMID: 30855280

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Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β-induced Serpine1.

Publications

Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β-induced Serpine1.

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