Abstract
Estrogen (E2) has been suggested to have a protective role in attenuating hepatocellular carcinoma (HCC) development. miRNAs have great potential as biomarkers and therapeutic agents owing to their ability to control gene expression. However, little is known about the mechanism underlying the protective role of E2 in hepatocarcinogenesis and the effects of E2 on apoptotic miRNAs expression. Using miRNA PCR array, we found more than 2-fold alteration was observed in 25 upregulated and 10 downregulated apoptotic miRNAs in E2-treated cells. Among these miRNAs, we found expression of miR-23a was related to p53 functional status in the male-derived liver cell-lines. We demonstrated that E2 via ERα transcriptionally activated miR-23a and p53 expression, and thus enhanced p53 activation of miR-23a expression. Moreover, miR-23a expression correlated inversely with the expression of target gene X-linked inhibitor of apoptosis protein (XIAP), but positively with the caspase-3/7 activity. Decreasing of XIAP might contribute to caspase-3 activity and cell apoptosis. Taken together, our findings reveal a novel E2-signaling mechanism in regulating miRNAs expression for controlling apoptosis in liver cells. Delineating the role of E2 in regulating the activation of p53 and miR-23a, expression in HCC is crucial to the understanding of the sex difference observed in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common malignant cancer and the third leading cause of cancer-related death in the world
We found miR-23a, miR-26b, miR-92 and miR-122 were significantly upregulated, whereas miR-143 and miR-17 were significantly downregulated when compared with untreated control cells (p < 0.01 for miR-143; p < 0.05 for miR-17) (Figure 1C)
Deregulation of several miRNAs have been reported to be involved in controlling apoptosis and carcinogenesis [12]
Summary
Hepatocellular carcinoma (HCC) is the fifth most common malignant cancer and the third leading cause of cancer-related death in the world. Epidemiological data indicate that regardless of etiology, the incidence of HCC is higher in males than in females, with a male to female ratio ranging between 3–5 to 1 [3]. This sex difference is found in the development of cirrhosis. This favourable outcome in female patients is attenuated after menopause [4]. Both epidemiologic evidence and results from animal studies have shown that estrogen (E2) may have a tumor protective role in female [4,5,6].
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