Abstract
Somatostatin and its analogues, which function by binding to somatostatin receptors (SSTRs) 1–5, play a protective role in liver cirrhosis. Hepatic SSTR-2 expression is up-regulated in subjects with liver cirrhosis. However, little is known about the mechanisms underlying this process. In the present study, we observed the up-regulation of hepatic SSTR-2 expression in thioacetamide (TAA)-induced cirrhotic rats and further showed that cyclooxygenase-2 (COX-2) might play a role in this process via the protein kinase C (PKC)–cAMP response element binding protein (CREB) signaling pathway. In vivo, the up-regulated SSTR-2 in liver cirrhosis was inhibited by the addition of a selective COX-2 inhibitor, such as celecoxib. In vitro, the up-regulation of COX-2 by either transfection with COX-2 plasmids or treatment with TAA increased levels of SSTR-2 and phosphorylated CREB (p-CREB) in the human hepatocyte cell line L02. Furthermore, the increase in SSTR-2 expression was inhibited by the addition of celecoxib and a PKC inhibitor. Moreover, for comparable DNA methylation levels in the region upstream of the hepatic SSTR-2 gene in normal and cirrhotic livers, DNA methylation may not contribute to the up-regulation of SSTR-2 expression in cirrhotic livers. In conclusion, the up-regulation of hepatic SSTR-2 might be induced by COX-2 via the PKC-CREB signaling pathway but is probably not induced by DNA methylation.
Highlights
Somatostatin (SST) is a polypeptide that is widely distributed throughout the human body
Hepatic SSTR-2 expression was up-regulated in the TAA-induced cirrhotic rat model
COX-2 might play a role in this process via the protein kinase C (PKC)-cAMP response element binding protein (CREB) signaling pathway in vivo and in vitro
Summary
Somatostatin (SST) is a polypeptide that is widely distributed throughout the human body. The SST analogue octreotide alleviates liver cirrhosis by directly inhibiting the synthesis of alpha-smooth muscle actin (α-SMA) and collagens in hepatic stellate cells (HSCs)[4,5,6]. The hepatic expression of SSTRs, SSTR-2, is up-regulated in subjects with liver cirrhosis[10]. Researchers have not determined whether DNA methylation at the SSTR-2 promoter region contributes to the up-regulation of SSTR-2 expression in the cirrhotic liver. Significant up-regulation of COX-2 and SSTR-2 was observed in the livers of cirrhotic patients compared with the levels in non-cirrhotic patients[26]. We explored the effect of DNA methylation and COX-2 on SSTR-2 expression. COX-2 may contribute to the up-regulation of hepatic SSTR-2 expression in subjects with liver cirrhosis
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