NOGOB receptor–mediated RAS signaling pathway is a target for suppressing proliferating hemangioma

Abstract

Infantile hemangioma is a vascular tumor characterized by the rapid growth of disorganized blood vessels followed by slow spontaneous involution. The underlying molecular mechanisms that regulate hemangioma proliferation and involution still are not well elucidated. Our previous studies reported that NOGOB receptor (NGBR), a transmembrane protein, is required for the translocation of prenylated RAS from the cytosol to the plasma membrane and promotes RAS activation. Here, we show that NGBR was highly expressed in the proliferating phase of infantile hemangioma, but its expression decreased in the involuting phase, suggesting that NGBR may have been involved in regulating the growth of proliferating hemangioma. Moreover, we demonstrate that NGBR knockdown in hemangioma stem cells (HemSCs) attenuated growth factor–stimulated RAS activation and diminished the migration and proliferation of HemSCs, which is consistent with the effects of RAS knockdown in HemSCs. In vivo differentiation assay further shows that NGBR knockdown inhibited blood vessel formation and adipocyte differentiation of HemSCs in immunodeficient mice. Our data suggest that NGBR served as a RAS modulator in controlling the growth and differentiation of HemSCs.

An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma

“…FPP and GGPP are directly involved in prenylation of various small GTPases, and other protein substrates including RAS family members (38). Importantly, RAS signaling has been implicated in IH (39). The R(+) propranolol mediated reduction in MVP genes and cholesterol biosynthesis may affect membrane fluidity and ruffling or activation of important signaling pathways by prenylation.…”

Infantile hemangioma: the common and enigmatic vascular tumor

“…HemSCs, HemECs, and hemangioma pericytes (HemPericytes), as well as macrophages and telocytes have been isolated from excised IH specimens and characterized ( Figure 1C ). HemSCs expressing CD133, VEGFR2, CD90, and integrin α-6 recapitulate hemangiogenesis when implanted in immune-deficient nude mice, as shown by rapid formation of human GLUT1 + vessels and appearance of human adipocytes at 4–8 weeks ( 32 – 37 ). In vivo and in vitro experiments demonstrate the ability of HemSCs to differentiate into endothelial cells, pericytes, and adipocytes.…”

Infantile hemangioma models: is the needle in a haystack?

“…NOGOB receptor (NGBR) is considered to be a specific receptor for NOGOB to stimulate endothelial cell migration and angiogenesis [ 37 ]. Hu et al [ 38 ] discovered that the NOGOB receptor NGBR is strongly expressed during the proliferative phase of IH but not during the degenerative phase, implying that NGBR may play a role in regulating the formation of vascular tumors. Furthermore, they investigated the effects of NGBR knockdown on the biological activity of HemSCs and discovered that NGBR knockdown can suppress cell proliferation, migration, and invasion, as well as lower the activation of the ras protein and receptor tyrosine kinase (RTK)-mediated signaling pathways (Fig.…”