한빛사 논문
Jin‑Woo Lee1,2,†, Jin Hur3,†, Yoo‑Wook Kwon1,2,†, Cheong‑Whan Chae1,2,†, Jae‑Il Choi1,2, Injoo Hwang1,2, Ji‑Yeon Yun1,2, Jin‑A Kang1,2, Young‑Eun Choi1,2, Young Hyun Kim1,2,7, Sang Eun Lee1,2, Cheol Lee4, Dong Hyun Jo5, Heeyoung Seok8, Byong Seung Cho9, Sung Hee Baek6 and Hyo‑Soo Kim1,2,7,10,*
1National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul, Republic of Korea. 2Center of Cell‑ and Bio‑Therapy (CBT), Seoul National University Hospital, Seoul, Republic of Korea. 3Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea. 4Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea. 5Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea. 6Creative Research Initiative Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul 151‑742, Republic of Korea. 7Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea. 8Genomics Core Facility, Department of Transdisciplinary Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea. 9ExoCoBio Inc, Gasan digital 1‑ro, Geumcheon‑gu, Seoul 08594, Republic of Korea. 10Department of Internal Medicine, Seoul National University Hospital, 101 Daehak‑ro, Jongno‑gu, Seoul 110‑744, Korea.
†Jin-Woo Lee, Jin Hur, Yoo-Wook Kwon and Cheong-Whan Chae have contributed equally to this work
*Correspondence to Hyo-Soo Kim.
Abstract
Background
Little is known about endogenous inhibitors of angiogenic growth factors. In this study, we identified a novel endogenous anti-angiogenic factor expressed in pericytes and clarified its underlying mechanism and clinical significance.
Methods
Herein, we found Kai1 knockout mice showed significantly enhanced angiogenesis. Then, we investigated the anti-angiogenic roll of Kai1 in vitro and in vivo.
Results
KAI1 was mainly expressed in pericytes rather than in endothelial cells. It localized at the membrane surface after palmitoylation by zDHHC4 enzyme and induced LIF through the Src/p53 pathway. LIF released from pericytes in turn suppressed angiogenic factors in endothelial cells as well as in pericytes themselves, leading to inhibition of angiogenesis. Interestingly, KAI1 had another mechanism to inhibit angiogenesis: It directly bound to VEGF and PDGF and inhibited activation of their receptors. In the two different in vivo cancer models, KAI1 supplementation significantly inhibited tumor angiogenesis and growth. A peptide derived from the large extracellular loop of KAI1 has been shown to have anti-angiogenic effects to block the progression of breast cancer and retinal neovascularization in vivo.
Conclusions
KAI1 from PC is a novel molecular regulator that counterbalances the effect of angiogenic factors.
Keywords : Anti-angiogenesis, Endogenous angiogenic growth factor inhibitor, KAI1 (CD82), Pericyte
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