Abstract
High levels of angiogenesis and resistance to apoptosis are major clinical features of hepatocellular carcinoma (HCC), a lethal disease with a high incidence worldwide. However, the precise mechanisms underlying these malignant properties remain unclear. Here, we demonstrated that acylglycerol kinase (AGK) is markedly overexpressed in HCC cell lines and clinical tissues. Immunohistochemical analysis of 245 clinical HCC specimens revealed patients with high levels of AGK expression had poorer overall survival compared to patients with low AGK expression. Furthermore, overexpressing AGK significantly enhanced angiogenesis and inhibited apoptosis in vitro and promoted the tumorigenicity of HCC cells in vivo; silencing endogenous AGK had the opposite effects. Importantly, AGK enhanced angiogenesis and inhibited apoptosis in HCC in part via activation of NF-κB signaling. Our findings provide new evidence that AGK plays an important role in promoting angiogenesis and providing resistance to apoptosis, thus AGK may represent a novel therapeutic target for HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common types of cancer and fourth leading cause of cancer-related deaths worldwide [1]
Realtime PCR and western blotting analyses showed that acylglycerol kinase (AGK) mRNA and protein expression were significantly upregulated in all eleven HCC cell lines tested compared to two immortalized normal liver cell lines (Figure 1A and Supplementary Figure 1A)
The expression of AGK sequentially increased in healthy liver, cirrhosis tissues and HCC (Figure 1E), suggesting that AGK may play a crucial role in the pathogenesis of HCC
Summary
Hepatocellular carcinoma (HCC) is one of the most common types of cancer and fourth leading cause of cancer-related deaths worldwide [1]. HCC cells proliferate rapidly and are highly resistant to apoptosis, resulting in significant insensitivity to chemotherapy [7]. The nuclear factor-κB (NF-κB) pathway plays important roles in the regulation of angiogenesis and cell survival and is constitutively activated in a variety of human cancers, including HCC [12,13,14,15,16]. Mutations in components of the NF-κB signaling system have been identified in multiple hematopoietic malignancies and are thought to result in cell-antonomous activation of NF-κB; extensive research has failed to identify NF-κB-activating mutations in most www.impactjournals.com/oncotarget solid tumor types including HCC [17, 19,20,21]. Identification of the causes that lead to aberrant activation of the NF-κB pathway in HCC is urgently required
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