title: T7 peptide inhibits angiogenesis via downregulation of angiopoietin-2 and autophagy.
abstract: Angiogenesis is required for the invasion, metastasis and chemoresistance of tumor cells. In addition to vascular endothelial cell growth factor (VEGF), angiopoietin-2 (Ang2) is considered to be a promising target for anti-angiogenic therapy. The T7 peptide, an active fragment of full-length tumstatin [the noncollagenous 1 domain of the type IV collagen α3 chain, α3(IV)NC1], has equivalent anti-angiogenic activity to that of full-length tumstatin. This study aimed to explore the mechanisms of the T7 peptide in the regulation of Ang2 expression in endothelial cells (ECs) as well as inhibition of angiogenesis and invasion of hepatocellular carcinoma cells. We also examined the role of autophagy in angiogenesis. Human umbilical vein endothelial cells (HUVECs) were incubated with endothelial cell medium (ECM)-2 in a hypoxia chamber to mimic hypoxic conditions. The recombinant T7 peptide inhibited the cell viability, tube formation and induced apoptosis of the HUVECs. The T7 peptide downregulated the protein expression of Ang2 by inhibiting phosphorylation of AKT under hypoxic conditions. The migration of HUVECs and invasion of HepG2 cells were inhibited by the T7 peptide via inhibition of Ang2 expression. EC autophagy was induced by the T7 peptide. Inhibition of autophagy enhanced the anti‑angiogenic activity of the T7 peptide by increasing EC apoptosis. In vivo, immunohistochemistry of VE-cadherin and CD31 showed that angiogenesis was decreased significantly by the T7 peptide in a nude mouse xenogeneic tumor model. In conclusion, the T7 peptide inhibited angiogenesis and exerted its antitumor effects by inhibition of Ang2, phosphorylation of AKT and matrix metalloproteinase-2 (MMP-2) regulated by Ang2. Furthermore, inhibition of autophagy may significantly enhance the anti-angiogenic activity of the T7 peptide.
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Fuhai
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, P.R. China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiu
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Honglong
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Zongzhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D024141:Collagen Type IV / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D024141:Collagen Type IV; D010446:Peptide Fragments; C555023:VPS51 protein, human; D033921:Vesicular Transport Proteins; C000591612:tumstatin (74-98); C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2