Dataset Information

Endothelial cell subtypes co-opt a TGFb/miR-30c-driven fibrinolytic pathway that supports tumor growth

ABSTRACT: In tumors, extravascular fibrin forms provisional scaffolds for angiogenesis but is degraded by fibrinolysis and replaced with collagen in a process that resembles wound healing. We report that fibrin-mediated angiogenesis is inhibited and tumor growth is delayed following postnatal deletion of TGFβR2 in the endothelium (TGFβR2iECKO). TGFβR2iECKO endothelial cells (ECs) fail to up-regulate the fibrinolysis inhibitor Serpine1/PAI-1 due, in part, to uncoupled TGFβ-mediated suppression of miR-30c. Bypassing TGFβR signaling with vascular tropic nanoparticles that deliver miR-30c AntagomiRs is sufficient to promote PAI-1-dependent tumor growth and increase fibrin abundance whereas miR-30c Mimics inhibit tumor growth and promote vascular-directed fibrinolysis in vivo. Using single cell RNA sequencing, we also show that subtypes of ECs in tumors show a spectrum of Serpine1 and uPar (urokinase receptor) expression suggesting functional diversity in ECs at the level of individual cells; furthermore, fresh EC isolates from lung and mammary tumor models have differential abilities to degrade fibrin and launch new vessel sprouts which is linked to their inverse expression patterns of miR-30c and Serpine1 (i.e. miR-30chiSerpine1lo ECs are poorly angiogenic and miR-30cloSerpine1hi ECs are highly angiogenic). Thus, EC subtypes co-opt physiological processes such as wound healing by subverting a previously uncharacterized vascular-directed fibrinolytic pathway that supports tumor growth.

ORGANISM(S): Mus musculus

PROVIDER: GSE118904 | GEO | 2019/05/14

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The clinical outcomes of hepatocellular carcinoma (HCC) remain dismal. Elucidating the molecular mechanisms for the progression of aggressive HCC holds the promise for developing novel intervention strategies. The transactivation response element RNA-binding protein (TRBP/TARBP2), a key component of microRNA (miRNA) processing and maturation machinery has exhibited to play conflicting roles in tumor development and progression. We sought to investigate the expression of TARBP2 in HCC using well-characterized HCC cell lines, patient-derived tissues and blood samples. Additionally, the potential prognostic and diagnostic value of TARBP2 in HCC were analyzed using Kaplan-Meier plots and ROC curve. Cell counting kit‐8 (CCK‐8), wound healing and transwell assays examined the ability of TARBP2 to induce cell proliferation, migration, and invasion in HCC cell lines. RNA sequencing was applied to identify the downstream elements of TARBP2. The interaction of potential targets of TARBP2, miR‐145 and serpin family E member 1 (SERPINE1), was assessed using luciferase reporter assay. TARBP2 expression was down-regulated in HCC cell lines relative to normal hepatocyte cells, with a similar pattern further confirmed in tissue and blood samples. Notably, the loss of TARBP2 was demonstrated to promote proliferation, migration, and invasion in HCC cell lines. Interestingly, the reduction of TARBP2 was shown to result in the upregulation of SERPINE1, also known as plasminogen activator inhibitor (PAI-1), which is a vital gene of the HIF-1 signaling pathway. Knockdown of SERPINE1 rescued the TARBP2-lost phenotype. Moreover, TARBP2 depletion induced the upregulation of SERPINE1 through reducing the processing of miR-145, which directly targets SERPINE1. Finally, overexpression of miR-145 repressed SERPINE1 and rescued the functions in sh-TARBP2 HCC cells. Our findings underscore a linear TARBP2-miR-145-SERPINE1 pathway that drives HCC progression, with the potential as a novel intervention target for aggressive HCC.

Dataset Information

Endothelial cell subtypes co-opt a TGFb/miR-30c-driven fibrinolytic pathway that supports tumor growth

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets