title: 14-3-3ζ up-regulates hypoxia-inducible factor-1α in hepatocellular carcinoma via activation of PI3K/Akt/NF-кB signal transduction pathway.
abstract: 14-3-3ζ protein, a member of 14-3-3 family, plays important roles in multiple cellular processes. Our previous study showed that 14-3-3ζ could bind to regulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is induced by hypoxia and a crucial factor for induction of tumor metastasis. Moreover, we also have confirmed the response of 14-3-3ζ to hypoxia in our unpublished data as well. Thus, in the present study, we attempted to reveal that whether the regulation effect of 14-3-3ζ on HIF-1α functioned in a similar pattern as hypoxia. Stable regulation of 14-3-3ζ in human HCC cell line SMMC-772 and HCC-LM3 was achieved. The regulation of 14-3-3ζ on HIF-1α mRNA transcription was evaluated by luciferase activity assay and quantitative real-time PCR (qPCR). The effect of 14-3-3ζ on the production of HIF-1α and pathways determining HIF-1α's response to hypoxia was assessed using western blotting assay. Our results showed that regulation of 14-3-3ζ expression influenced the activity of HIF-1α, phosphatidyl inositol 3-kinase (PI3K), Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and nuclear factor kappa B (NF-кB). Blocking of these pathways using indicated inhibitors revealed that 14-3-3ζ enhanced the production of HIF-1α via the activation of PI3K/Akt/NF-кB pathway, which was identical to hypoxia induced HIF-1α expression. For the first time, our study described the key role of 14-3-3ζ in the HIF-1α production in HCC cells. And the molecule exerted its function on HIF-1α both by directly binding to it and via PI3K/Akt/NF-кB signal transduction pathway.
authors.affiliation: Department of Hepatobiliary Surgery, The General Hospital of Shenyang Military Area CommandShenyang 110016, People's Republic of China; Post-Doctoral Station, The General Hospital of Shenyang Military Area CommandShenyang 110016, People's Republic of China.
authors.forename: Yufu
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Hepatobiliary Surgery, The General Hospital of Shenyang Military Area Command Shenyang 110016, People's Republic of China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Lv
authors.affiliation: Department of Hepatobiliary Surgery, The General Hospital of Shenyang Military Area Command Shenyang 110016, People's Republic of China.
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary Surgery, The General Hospital of Shenyang Military Area Command Shenyang 110016, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Hepatobiliary Surgery, The General Hospital of Shenyang Military Area Command Shenyang 110016, People's Republic of China.
authors.forename: Bichao
authors.initials: B
authors.lastname: Luo
authors.affiliation: Department of Hepatobiliary Surgery, The General Hospital of Shenyang Military Area Command Shenyang 110016, People's Republic of China.
authors.forename: Wenping
authors.initials: W
authors.lastname: Zhou
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D048948:14-3-3 Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C572235:YWHAZ protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: 14-3-3ζ; Akt; hypoxia; hypoxia-inducible factor-1α; nuclear factor kappa B; phosphatidyl inositol 3-kinase