title: Up-regulation of urotensin II and its receptor contributes to human hepatocellular carcinoma growth via activation of the PKC, ERK1/2, and p38 MAPK signaling pathways.
abstract: Urotensin II (UII) and its receptor (UTR) have mitogenic effects on tumor growth. Our previous study demonstrated that the UII/UTR system is up-regulated in dithyinitrosamine-induced precancerous rat liver lesions. However, its role in human hepatocellular carcinoma remains unknown. In this study, the mRNA and protein expression of UII and its receptor (UTR) in human hepatocellular carcinoma samples and in the BEL-7402 human hepatoma cell line were evaluated. In addition, the effect of exogenous UII on the pathways that regulate proliferation in BEL-7402 cells in vitro were determined. Liver sections were subjected to immunohistochemical staining. mRNA expression was detected by real-time polymerase chain reaction analysis, and protein levels were evaluated by western blotting. Proliferating cells were detected by BrdU incorporation. The expression of UII/UT mRNA and protein significantly increased in human hepatocellular carcinoma samples, and in BEL-7402 cells. Administration with UII increased the phosphorylation of protein kinase C (PKC), extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein kinases (p38 MAPK). Furthermore, GF109203x, PD184352, and SB203580 partially abolished UII-induced proliferation of BEL-7402 cells. These results provide the first evidence that up-regulation of the UII/UT system may enhance proliferation of the human hepatoma cell line at least in part via PKC, ERK1/2, and p38 MAPK signaling pathways, and may provide novel therapeutic targets for inhibiting human hepatocellular carcinoma.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing 100069, China. yxt20053@sina.com.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Yu
authors.affiliation: Department of Pathology, Peking Union Medical Hospital, Beijing 100692, China. wpy1120@163.com.
authors.forename: Peng-Yan
authors.initials: PY
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Beijing Jishuitan Hospital, Beijing 100031, China. shi-zm@163.com.
authors.forename: Zheng-Ming
authors.initials: ZM
authors.lastname: Shi
authors.affiliation: Department of Pathology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China. bugu_bird_logo@163.com.
authors.forename: Kun
authors.initials: K
authors.lastname: Dong
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing 100069, China. ping-feng1002@163.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Feng
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing 100069, China. whxdy@sina.com.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing 100069, China. xjwang@ccmu.edu.cn.
authors.forename: Xue-Jiang
authors.initials: XJ
authors.lastname: Wang
mesh_terms: D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014579:Urotensins / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014579:Urotensins; C029677:urotensin II; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases