title: Urotensin-II-Mediated Reactive Oxygen Species Generation via NADPH Oxidase Pathway Contributes to Hepatic Oval Cell Proliferation.
abstract: Urotensin II (UII), a somatostatin-like cyclic peptide, is involved in tumor progression due to its mitogenic effect. Our previous study demonstrated that UII and its receptor UT were up-regulated in human hepatocellular carcinoma (HCC), and exogenous UII promoted proliferation of human hepatoma cell line BEL-7402. Hepatic progenitor cell (HPCs) are considered to be one of the origins of liver cancer cells, but their relationship with UII remains unclear. In this work, we aimed to investigate the effect of UII on ROS generation in HPCs and the mechanisms of UII-induced ROS in promoting cell proliferation. Human HCC samples were used to examine ROS level and expression of NADPH oxidase. Hepatic oval cell line WB-F344 was utilized to investigate the underlying mechanisms. ROS level was detected by dihydroethidium (DHE) or 2', 7'-dichlorofluorescein diacetate (DCF-DA) fluorescent probe. For HCC samples, ROS level and expression of NADPH oxidase were significantly up-regulated. In vitro, UII also increased ROS generation and expression of NADPH oxidase in WB-F344 cells. NADPH oxidase inhibitor apocynin pretreatment partially abolished UII-increased phosphorylation of PI3K/Akt and ERK, expression of cyclin E/cyclin-dependent kinase 2. Cell cycle was then analyzed by flow cytometry and UII-elevated S phase proportion was inhibited by apocynin pretreatment. Finally, bromodeoxyuridine (Brdu) incorporation assay showed that apocynin partially abolished UII induced cell proliferation. In conclusion, this study indicates that UII-increased ROS production via the NADPH oxidase pathway is partially associated with activation of the PI3K/Akt and ERK cascades, accelerates G1/S transition, and contributes to cell proliferation. These results showed that UII plays an important role in growth of HPCs, which provides novel evidence for the involvement of HPCs in the formation and pathogenesis of HCC.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.|Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Capital Medical University, Beijing, China.
authors.forename: XiaoTong
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pathology, Peking Union Medical Hospital, Beijing, China.
authors.forename: PengYan
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Beijing Jishuitan Hospital, Beijing, China.
authors.forename: ZhengMing
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Pathology, Beijing Youan Hospital, Capital Medical University, Beijing, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Dong
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.|Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Capital Medical University, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Feng
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: HongXia
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.|Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Capital Medical University, Beijing, China.
authors.forename: XueJiang
authors.initials: X
authors.lastname: Wang
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014579:Urotensins / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D019927:Cyclin E; D010446:Peptide Fragments; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D014579:Urotensins; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-; C029677:urotensin II; C056165:acetovanillone; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases