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

• Published in: JCI insight 2021-02, Vol.6 (3)
• Main Authors: Hu, Wenquan, Liu, Zhong, Salato, Valerie, North, Paula E, Bischoff, Joyce, Kumar, Suresh N, Fang, Zhi, Rajan, Sujith, Hussain, M Mahmood, Miao, Qing R
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Cycle Checkpoints - genetics; Cell Differentiation; Cell Movement - genetics; Cell Proliferation - genetics; Gene Expression; Gene Knockdown Techniques; Hemangioma - metabolism; Hemangioma - pathology; Hemangioma - therapy; Humans; In Vitro Techniques; Infant; Male; Mice; Mice, Nude; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; ras Proteins - metabolism; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Signal Transduction; Tumor Cells, Cultured; Vascular biology; Xenograft Model Antitumor Assays
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.142299

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.