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.
Highlights
Urotensin II (UII), a somatostatin-like cyclic peptide, was first isolated from the urophysis of teleost fishes, and later from mammals and humans [1,2]
Our previous study demonstrated that the UII/UT system is up-regulated in dithyinitrosamine-induced rat precancerous liver lesions [12]; no report has been published on the expression of this system in human hepatocellular carcinoma
In this study, using a combined in vivo and in vitro approach, the expression of the UII/UT system in human hepatocellular carcinoma and in the BEL-7402 human hepatocellular cell line were investigated, and the effect of exogenous UII on the phosphorylation of protein kinase C (PKC), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) was examined to determine the possible mechanism underlying the pathogenesis of hepatocellular carcinoma
Summary
Urotensin II (UII), a somatostatin-like cyclic peptide, was first isolated from the urophysis of teleost fishes, and later from mammals and humans [1,2]. UII was detected as a potent vasoconstrictor in mammalians, but it has since been reported to stimulate calcium mobilization in cells stably transfected with its receptor [6]. UII has been reported to be involved in the pathogenesis of some tumors. UII significantly stimulates the proliferation of some tumor cells, including SW-13 cells [9], VMRC-RCW renal cell carcinoma cells [9], and human pheochromocytoma cells [10]. Our previous study demonstrated that the UII/UT system is up-regulated in dithyinitrosamine-induced rat precancerous liver lesions [12]; no report has been published on the expression of this system in human hepatocellular carcinoma. In this study, using a combined in vivo and in vitro approach, the expression of the UII/UT system in human hepatocellular carcinoma and in the BEL-7402 human hepatocellular cell line were investigated, and the effect of exogenous UII on the phosphorylation of PKC, ERK1/2, and p38 MAPK was examined to determine the possible mechanism underlying the pathogenesis of hepatocellular carcinoma
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