Abstract 775: Identification of activated signal transduction pathways and molecules in the HMGB-1 induced angiogenesis

Abstract

Abstract High-mobility group box-1 (HMGB-1) is a highly conserved protein playing various roles both in the nucleus and cytosol and known to be expressed in almost all types of mammalian cells. Secreted HMGB-1 has been most intensively studied and reported as an immune cell derived cytokine regulating systemic inflammation, signal transduction, and activation of endothelial cells (EC). Especially, HMGB-1 over-expression is now considered as a hallmark in cancers based on its involvement in cell proliferation, inflammatory microenvironment, invasion, metastasis, and sustained angiogenesis. Numerous studies have shown that secreted HMGB-1 directly or indirectly promotes angiogenesis by activation of ECs. However, mechanisms of HMGB-1 mediated angiogenesis have not yet been fully understood, especially, in terms of genomic changes caused by HMGB-1 treatment. Moreover, differences between vascular endothelial growth factor (VEGF) mediated and HMGB-1 mediated angiogenesis have not been studied. To explore the roles of HMGB-1 in angiogenesis, we first confirmed whether HMGB-1 treatment renders ECs angiogenic by evaluating proliferation, migration, wound-healing, and tubule formation of ECs after HMGB-1 treatment. In addition, we performed gene expression microarray to clarify how HMGB-1 treatment induced EC activation at various time points and subsequent angiogenic features according to time-dependent gene expression changes. We show that HMGB-1 treatment induces proangiogenic features to ECs such as stimulation of tubule formation, promotion of proliferation, and accelerated wound healing. By analysis of microarray data, we found that VEGF and HMGB-1 commonly promoted the activation of MAPK, cell proliferation, and wound healing pathways which directly regulate angiogenesis. On the other hand, axon guidance, gap junction, P53 signaling, cell cycle, and cell differentiation pathways were specifically up-regulated by HMGB-1. Taken together, HMGB-1 leads to angiogenesis via upregulation of both angiogenic and nonangiogenic genes. Citation Format: Yujin Kwon, Sujin Shin, Won Kyu Kim, Hoguen Kim. Identification of activated signal transduction pathways and molecules in the HMGB-1 induced angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 775. doi:10.1158/1538-7445.AM2017-775