title: Latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus promotes angiogenesis through targeting notch signaling effector Hey1.
abstract: Notch signaling has been implicated in the pathogenesis of Kaposi sarcoma. Kaposi sarcoma is an angioproliferative neoplasm that originates from Kaposi sarcoma-associated herpesvirus (KSHV) infection. Previously, we showed that the KSHV LANA protein can stabilize intracellular Notch in KSHV-infected tumor cells and promote cell proliferation. However, whether Notch signaling functions in pathologic angiogenesis of Kaposi sarcoma remains largely unknown. Hey1, an essential downstream effector of the Notch signaling pathway, has been demonstrated to play a fundamental role in vascular development. In the present study, we performed whole transcriptome, paired-end sequencing on three patient-matched clinical Kaposi sarcoma specimens and their corresponding adjacent stroma samples, with an average depth of 42 million reads per sample. Dll4, Hey1, and HeyL displayed significant upregulation in Kaposi sarcoma. Further verification based on immunohistochemistry analysis demonstrated that Hey1 was indeed highly expressed in Kaposi sarcoma lesions. Using the Matrigel plug assay, we showed that downregulation of Hey1 and γ-secretase inhibitor treatment caused dramatic reduction in the formation of new blood vessels in mice. Interestingly, LANA was responsible for the elevated level of Hey1 through inhibition of its degradation. Importantly, Hey1 stabilized by LANA promoted the neoplastic vasculature. Taken together, our data suggest that hijacking of the proangiogenic property of Hey1 by LANA is an important strategy utilized by KSHV to achieve pathologic angiogenesis and that Hey1 is a potential therapeutic target in Kaposi sarcoma.
authors: Authors' Affiliations: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai; and The First Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
authors: Xing
authors: X
authors: Wang
authors: Zhiheng
authors: Z
authors: He
authors: Tian
authors: T
authors: Xia
authors: Xiaofan
authors: X
authors: Li
authors: Deguang
authors: D
authors: Liang
authors: Xianzhi
authors: X
authors: Lin
authors: Hao
authors: H
authors: Wen
authors: Ke
authors: K
authors: Lan
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000209:etiology*; D009687:Nuclear Proteins / Q000502:physiology*; D051880:Receptors, Notch / Q000502:physiology; D012097:Repressor Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012514:Sarcoma, Kaposi / Q000098:blood supply* / Q000628:therapy; D015398:Signal Transduction
chemical_list: D000956:Antigens, Viral; D051792:Basic Helix-Loop-Helix Proteins; D009687:Nuclear Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; C405694:Hairy, HRT1 protein; C109540:latency-associated nuclear antigen