title: Knockdown of HIF-1α and IL-8 induced apoptosis of hepatocellular carcinoma triggers apoptosis of vascular endothelial cells.
abstract: A local hypoxic microenvironment is one of the most important characteristics of solid tumors. Hypoxia inducible factor-1α (HIF-1α) and Interleukin-8 (IL-8) activate tumor survival from hypoxic-induced apoptosis in each pathway. This study aimed to evaluate whether knockdown of HIF-1α and IL-8 induced apoptosis of the hepatocellular carcinoma (HCC) and endothelial cell lines. HCC cell lines were infected with adenovirus-expressing shRNA for HIF-1α and IL-8 and maintained under hypoxic conditions (1% O2, 24 h). The expression levels of HIF-1α and both apoptotic and growth factors were examined by real-time quantitative PCR and western blot. We also investigated apoptosis by TUNEL assay (FACS and Immunofluorescence) and measured the concentration of cytochrome C. Inhibition of HIF-1α and IL-8 up-regulated the expression of apoptotic factors while downregulating anti-apoptotic factors simultaneously. Knockdown of HIF-1α and IL-8 increased the concentration of cytochrome C and enhanced DNA fragmentation in HCC cell lines. Moreover, culture supernatant collected from the knockdown of HIF-1α and IL-8 in HCC cell lines induced apoptosis in human umbilical vein endothelial cells under hypoxia, and the expression of variable apoptotic ligand increased from HCC cell lines, time-dependently. These data suggest that adenovirus-mediated knockdown of HIF-1α and IL-8 induced apoptosis in HCC cells and triggered apoptosis of vascular endothelial cells.
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. drpjy@yuhs.ac.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. drpjy@yuhs.ac.|Yonsei Liver Center, Yonsei University Health System, Seoul, Korea. drpjy@yuhs.ac.
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Wonseok
authors.initials: W
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Yonsei Liver Center, Yonsei University Health System, Seoul, Korea.
authors.forename: Seung Up
authors.initials: SU
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Yonsei Liver Center, Yonsei University Health System, Seoul, Korea.
authors.forename: Do Young
authors.initials: do Y
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Yonsei Liver Center, Yonsei University Health System, Seoul, Korea.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Simon Wonsang
authors.initials: SW
authors.lastname: Ro
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.|Yonsei Liver Center, Yonsei University Health System, Seoul, Korea.
authors.forename: Kwang-Hyub
authors.initials: KH
authors.lastname: Han
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; D017077:Culture Media, Conditioned; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D034741:RNA, Small Interfering; D051020:bcl-X Protein; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Apoptosis; Death signal ligands; FACs-TUNEL; Hypoxia inducible factor-1α; Interleukin-8; Tumor xenograft model