title: Synergistic tumor suppression by adenovirus-mediated inhibitor of growth 4 and interleukin-24 gene cotransfer in hepatocarcinoma cells.
abstract: Inhibitor of growth 4 (ING4) is a novel member of ING tumor suppressor family and has apparent tumor-suppressive effect. Interleukin-24 (IL-24) as a unique cytokine-tumor suppressor displays ubiquitous antitumor property and tumor-specific killing activity. Multigene-based combination therapy may be an effective practice in cancer gene therapy. The therapeutic potential of a conjunction of ING4 and IL-24 for cancers is still elusive. This study evaluated the combined effect on SMMC-7721 and HepG2 human hepatocarcinoma cells by adenovirus-mediated ING4 and IL-24 coexpression (Ad-ING4-IL-24) and also elucidated its underlying molecular mechanism. It was demonstrated that Ad-ING4-IL-24 induced synergistic growth inhibition, apoptosis, invasion suppression, as well as an enhanced effect on upregulation of P21, P27, Fas, FasL, FADD, Bad, Bax, Bak, cleaved Bid, cleaved Caspase-8, -9, and -3, and cleaved PARP, downregulation of Bcl-2, Bcl-X(L), matrix metalloproteinase (MMP)-2, 9, vascular endothelial growth factor (VEGF), IL-8, CD34, and microvessel density, and cytochrome c release from mitochondria into cytosol in in vitro SMMC-7721 and HepG2 hepatocarcinoma cells and/or in vivo SMMC-7721 hepatocarcinoma subcutaneous xenografted tumors in athymic nude mice. The in vitro and in vivo synergistic antitumor activity elicited by Ad-ING4-IL-24 was closely associated with the cooperative activation of extrinsic and intrinsic apoptotic pathways and reduced proangiogenic factors' production of VEGF and IL-8, leading to synergistic inhibition of tumor angiogenesis. Thus, results indicate that cancer gene therapy combining two or more tumor suppressors such as ING4 and IL-24 may constitute a novel and effective therapeutic strategy for hepatocarcinoma and other cancers.
authors: Cell and Molecular Biology Institute, College of Medicine, Soochow University, Suzhou, China.
authors: Yufeng
authors: Y
authors: Xie
authors: Haitao
authors: H
authors: Lv
authors: Weihua
authors: W
authors: Sheng
authors: Jingcheng
authors: J
authors: Miao
authors: Jim
authors: J
authors: Xiang
authors: Jicheng
authors: J
authors: Yang
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D002461:Cell Line, Transformed; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D000099180:Interleukin-24
chemical_list: D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D016209:Interleukin-8; D007378:Interleukins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D000099180:Interleukin-24; C483230:ING4 protein, human; C467484:VEGFA protein, human