title: Vasohibin 2 is transcriptionally activated and promotes angiogenesis in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) typically relies on angiogenesis for its malignant behavior, including growth and metastasis. Vasohibin 2 (VASH2) was previously identified as an angiogenic factor, but its role in tumorigenesis is unknown. Using quantitative PCR and western blot analyses, we found that VASH2 is overexpressed in HCC cells and tissues. Using chromatin immunoprecipitation, we detected histone modifications at the putative VASH2 promoter, with increased H3K4 trimethylation and H3 acetylation and decreased H3K27 trimethylation, suggesting that epigenetic mechanisms are responsible for the deregulated VASH2 transcription in HCC. Knockdown of VASH2 via siRNA inhibited the proliferation of the hepatoma cell lines by delaying cell cycle progression and increasing apoptosis. Importantly, we found VASH2 secreted in the culture supernatant, and co-expression of its secretory chaperone small vasohibin-binding protein (SVBP) further enhanced VASH2 secretion. The supernatant from HepG2 cells expressing VASH2 enhanced the proliferation, migration and tube formation of human umbilical vein endothelial cells, and knockdown of VASH2 significantly inhibited these effects. In an in vivo study using a nude mouse model, we found that exogenous VASH2 significantly contributed to tumor growth, microvessel density and hemoglobin concentration in the tumors. Further analyses showed that the VASH2-mediated increase in the transcription of fibroblast growth factor-2, vascular endothelial growth factor and vasohibin 1 may be the mechanism underlying these effects. Taken together, these data indicate that VASH2 is abnormally expressed in HCC cells as a result of histone modifications and that VASH2 contributes to the angiogenesis in HCC via an SVBP-mediated paracrine mechanism. These results indicate a novel and important role for VASH2 in HCC angiogenesis and malignant transformation.
authors.affiliation: Department of General Surgery, First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Xue
authors.forename: W
authors.initials: W
authors.lastname: Gao
authors.forename: B
authors.initials: B
authors.lastname: Sun
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: B
authors.initials: B
authors.lastname: Han
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Sun
authors.forename: J
authors.initials: J
authors.lastname: Wei
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.forename: Y
authors.initials: Y
authors.lastname: Sekido
authors.forename: Y
authors.initials: Y
authors.lastname: Miao
authors.forename: Y
authors.initials: Y
authors.lastname: Kondo
mesh_terms: D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D042501:Angiogenic Proteins; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D034741:RNA, Small Interfering; C554361:SVBP protein, human; C574858:VASH2 protein, human