title: Inhibition of hepatocellular carcinoma growth and angiogenesis by dual silencing of NET-1 and VEGF.
abstract: Simultaneous silencing of multiple up-regulated genes is an attractive and viable strategy to treat many incurable diseases including cancer. Herein we used dual gene targeted siRNA (DGT siRNA) conjugate composed of NET-1 and VEGF siRNA sequences in the same backbone could inhibit growth and angiogenesis HCC. DGT siRNA showed a further down regulation on VEGF mRNA and protein levels compared with NET-1 siRNA or VEGF siRNA, but not on NET-1 expression. It also exhibited greater suppression on proliferation and trigger of apoptosis in HepG2 cells than NET-1 siRNA or VEGF siRNA; this could be explained by the significant down regulation of cyclin D1 and Bcl-2. A lower level of ANG2 mRNA and protein was detected in HUVEC cultured with supernatant of HepG2 cells treated with DGT siRNA than that of VEGF siRNA or NET-1 siRNA, resulting in much more inhibited angiogenesis of HUVEC. Tumor growth was inhibited and microvessel density dropped in the xenograft tumor models compared to the untreated controls. NET-1 and VEGF silencing play a key role in inhibiting hepatocellular cell proliferation, promoting apoptosis, and reducing angiogenesis. Simultaneous silencing of NET-1 and VEGF using DGT siRNA construct may provide an advantageous alternative in development of therapeutics for Hepatocellular carcinoma.
authors: Department of Pathological Anatomy, Nantong University, Nantong, People's Republic of China.
authors: Yuan-Yuan
authors: YY
authors: Wu
authors: Li
authors: L
authors: Chen
authors: Gui-Lan
authors: GL
authors: Wang
authors: Yi-Xin
authors: YX
authors: Zhang
authors: Jia-Ming
authors: JM
authors: Zhou
authors: Song
authors: S
authors: He
authors: Jing
authors: J
authors: Qin
authors: Yuan-Yuan
authors: YY
authors: Zhu
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology*; D015513:Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D042702:Angiopoietin-2; C099763:NET1 protein, human; D015513:Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1; D040301:Vascular Endothelial Growth Factor Receptor-2
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