Abstract
Cyclooxygenase-2 (COX-2) expression has been detected in human hepatoma cell lines and in human hepatocellular carcinoma (HCC); however, the contribution of COX-2 to the development of HCC remains controversial. COX-2 expression is higher in the non-tumoral tissue and inversely correlates with the differentiation grade of the tumor. COX-2 expression depends on the interplay between different cellular pathways involving both transcriptional and post-transcriptional regulation. The aim of this work was to assess whether COX-2 could be regulated by microRNAs in human hepatoma cell lines and in human HCC specimens since these molecules contribute to the regulation of genes implicated in cell growth and differentiation. Our results show that miR-16 silences COX-2 expression in hepatoma cells by two mechanisms: a) by binding directly to the microRNA response element (MRE) in the COX-2 3′-UTR promoting translational suppression of COX-2 mRNA; b) by decreasing the levels of the RNA-binding protein Human Antigen R (HuR). Furthermore, ectopic expression of miR-16 inhibits cell proliferation, promotes cell apoptosis and suppresses the ability of hepatoma cells to develop tumors in nude mice, partially through targeting COX-2. Moreover a reduced miR-16 expression tends to correlate to high levels of COX-2 protein in liver from patients affected by HCC. Our data show an important role for miR-16 as a post-transcriptional regulator of COX-2 in HCC and suggest the potential therapeutic application of miR-16 in those HCC with a high COX-2 expression.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and has an increasing incidence in western countries [1]
To examine whether COX-2 expression is under the control of miRNAs, we determined the expression pattern of COX-2 and selected miRNAs in four hepatoma (HCC) cell lines (HepG2, PLC/PRF/5, HuH-7, Hep3B) and in a cell line derived from human liver embryo (WRL68), using human hepatocytes (HH) as control (Fig. 1A)
Our results show that miR-16 directly silences COX-2 expression in hepatoma cells and indirectly through the downregulation of Human Antigen R (HuR)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and has an increasing incidence in western countries [1]. COX-1 is constitutively expressed in many tissues, whereas COX-2 is induced by a variety of stimuli such as growth factors, pro-inflammatory stimuli, hormones and other cellular stresses [4]. Adult hepatocytes fail to induce COX-2 expression regardless of the pro-inflammatory factors used [5,6]. Our group and others demonstrated that partial hepatectomy (PH) [7,8] induced COX-2 in hepatocytes and contributed to the progression of cell cycle after PH. In addition to liver regeneration after PH or hepatotoxic agents, expression of COX-2 has been detected in animal models of cirrhosis [9], in human hepatoma cell lines [10,11], in human HCC [12] and after HBV and HCV infection [13,14]
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