Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide and ranks third in overall global cancer-related mortality rates. Importantly, in this study gene expression data demonstrate that prolonged survival in HCC patients is associated with increased regucalcin gene expression. Regucalcin has been shown to play a pivotal role as a transcription repressor and diminished expression or activity of regucalcin may play a key role in the development of human carcinogenesis. Indeed, overexpression of regucalcin suppressed the proliferation, cell death, and migration of human HCC HepG2 cells in vitro. Mechanistically, regucalcin induced G1 and G2/M phase cell cycle arrest of HepG2 cells through suppression of multiple signaling pathways including Ras, Akt, MAP kinase and SAPK/JNK and by increasing the tumor suppressors p53 and Rb. Furthermore, the oncogenes c-fos and c-myc were suppressed by overexpression of regucalcin, and overexpression of regucalcin caused an increase in p21 and a decrease in NF-κB p65 and β-catenin. These findings suggest that regucalcin may play a potential role as a suppressor of human HCC, and that diminished expression of regucalcin may predispose patients to development of HCC. Overexpression of regucalcin may constitute a novel therapeutic approach to treating HCC.
Highlights
Hepatocellular carcinoma (HCC), the most common primary liver cancer, is one of the most prevalent malignant diseases worldwide, and the third most common cause of cancer-related death [1,2]
Overall regucalcin expression was visually reduced in HCC patients as compared with that of tissues derived from normal liver (Fig. 1A)
Higher regucalcin gene expression was found to prolong survival in HCC patients (Fig. 1D). These findings support the notion that suppression of regucalcin gene expression partly contributes to the development of carcinogenesis in human HCC cells and leads to a worse clinical outcome
Summary
Hepatocellular carcinoma (HCC), the most common primary liver cancer, is one of the most prevalent malignant diseases worldwide, and the third most common cause of cancer-related death [1,2]. HCC originates on a background of cirrhosis, a chronic and diffuse hepatic disease, which results from continuous liver injury and regeneration [3,4]. HCC is a cancer with a poor prognosis. The prognosis of advanced HCC remains poor in spite of the development of novel therapeutic strategies. In recent years, improved knowledge of the oncogenic processes and signaling pathways that regulate tumor cell proliferation, differentiation, angiogenesis, invasion and metastasis has led to the identification of several potential therapeutic targets, which have driven the development of molecularly targeted therapies [9,10]. The most effective therapeutic tool for advanced non-resectable HCC, which can slightly improve patient survival, is based on the multikinase inhibitor sorafenib [11,12]. New perspectives in cancer treatment have appeared recently with the advent of the microRNAs, a novel class of non-coding small RNAs [13]
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