Myc‐associated zinc finger protein (MAZ) is regulated by miR‐125b and mediates VEGF‐induced angiogenesis in glioblastoma

Abstract

In patients with glioblastomas, vascular endothelial growth factor (VEGF) is a key mediator of tumor-associated angiogenesis. Glioblastomas are notorious for their capacity to induce neovascularization, driving continued tumor growth. Here we report that miR-125b is down-regulated in glioblastoma-associated endothelial cells, resulting in increased expression of its target, myc-associated zinc finger protein (MAZ), a transcription factor that regulates VEGF. The down-regulation of miR-125b was also observed on exposure of endothelial cells to glioblastoma-conditioned medium or VEGF, resulting in increased MAZ expression. Further analysis revealed that inhibition of MAZ accumulation by miR-125b, or by MAZ-specific shRNAs, attenuated primary human brain endothelial cell migration and tubule formation in vitro, phenomena considered to mimick angiogenic processes in vitro. Moreover, MAZ expression was elevated in brain blood vessels of glioblastoma patients. Altogether these results demonstrate a functional feed-forward loop in glioblastoma-related angiogenesis, in which VEGF inhibits the expression of miR-125b, resulting in increased expression of MAZ, which in its turn causes transcriptional activation of VEGF. This loop is functionally impeded by the VEGF receptor inhibitor vandetanib, and our results may contribute to the further development of inhibitors of tumor-angiogenesis.

Epigenetic Profile of Human Adventitial Progenitor Cells Correlates With Therapeutic Outcomes in a Mouse Model of Limb Ischemia

“…Furthermore, we investigated the expression levels of 2 microRNAs, namely microRNA-132, which we have previously reported to be implicated in the in vivo healing effects of SV-APCs in a mouse model of myocardial infarction, 9 and microRNA-125b, which plays crucial roles in many different cellular processes, such as cell differentiation, proliferation, and apoptosis, associated with angiogenesis through inhibition of its target gene MAZ. 16,[19][20][21] Consistent with an antiangiogenic action of microRNA-125, we found this microRNA to be inversely correlated with capillary density and arteriole density outcomes, whereas no association was found for microRNA-132 (Table VI in the online-only Data Supplement). Finally, we verified the expression of 3 genes emerging from ontology analysis of gene array data, namely prostaglandin-endoperoxide synthase 2/cyclooxygenase 2, the enzyme that converts arachidonic acid to prostaglandin H2, chitinase-3-like protein 1, also known as cartilage glycoprotein 39 (YKL-40), which is implicated in mural cell-mediated angiogenesis, 22 and RUNX1, which has been associated with proangiogenic activity of endothelial progenitor cells.…”

“…MAZ is a zinc finger transcription factor that binds to GpCrich cis-elements in the promoter regions of numerous mammalian genes and is also able to recruit different proteins, such as methylases and acetylases, to the transcriptional complex, thereby acting as an initiator or terminator of transcription. 31 The transcription factor has been implicated in VEGF-induced angiogenesis 16,32,33 ; this effect being negatively controlled by microRNA-125b, of which MAZ is an inhibitory target. 16 Of note, we found that the expression of microRNA-125b in SV-APCs is inversely correlated with their ability to induce reparative vascularization in the mouse LI model.…”

“…14,15 Moreover, 536 genes associated with blood flow, 2805 genes associated with capillary density, and 460 genes associated with arteriole counts are regulated by MYCassociated zinc finger protein (MAZ), which is involved in cell proliferation and mediates vascular endothelial growth factor (VEGF)-induced angiogenesis. 16 Hence, interference of DNA methylation with KROX/EGR1 and MAZ might result in large effects on gene transcription and possibly on promotion of tissue repair by SV-APCs.…”

Elevated microRNA-125b levels predict a worse prognosis in HER2-positive breast cancer patients

“…It has been demonstrated that miR-125b is dysregulated in a broad variety of tumors. It is downregulated in head and neck tumors, oral squamous cell carcinomas, osteosarcomas and gliomas (20)(21)(22)(23). Hypermethylation in the promoter regions of miR-125b appears to block miR-125b expression levels in ovarian cancer (24) and breast cancer (10).…”

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

“…This downregulation results in increased expression of its target, myc‐associated zinc finger protein (MAZ), a transcription factor that regulates VEGF. Decreased expression of miR‐125b in target cells promotes vascularization of tumors 80.…”