Abstract
In this study, we investigated the role of embryonic gene Cripto-1 (CR-1) in hepatocellular carcinoma (HCC) using hepatocyte-specific CR-1-overexpressing transgenic mice. The expression of truncated 1.7-kb CR-1 transcript (SF-CR-1) was significantly higher than the full-length 2.0-kb CR-1 transcript (FL-CR-1) in a majority of HCC tissues and cell lines. Moreover, CR-1 mRNA and protein levels were significantly higher in HCC tissues than adjacent normal liver tissues. Hepatocyte-specific over-expression of CR-1 in transgenic mice enhanced hepatocyte proliferation after 2/3 partial hepatectomy (2/3 PHx). CR-1 over-expression significantly increased in vivo xenograft tumor growth of HCC cells in nude mice and in vitro HCC cell proliferation, migration, and invasion. CR-1 over-expression in the transgenic mouse livers deregulated HCC-related signaling pathways such as AKT, Wnt/β-catenin, Stat3, MAPK/ERK, JNK, TGF-β and Notch, as well as expression of HCC-related genes such as CD5L, S100A8, S100A9, Timd4, Orm2, Orm3, PDK4, DMBT1, G0S2, Plk2, Plk3, Gsta1 and Gsta2. However, histological signs of precancerous lesions, hepatocyte dysplasia or HCC formation were not observed in the livers of 3-, 6- or 8-month-old hepatocyte-specific CR-1-overexpressing transgenic mice. These findings demonstrate that liver-specific CR-1 overexpression in transgenic mice deregulates signaling pathways and genes associated with HCC.
Highlights
Hepatocellular carcinoma (HCC) accounts for 70–85% of all primary liver cancer cases and is one of the most common malignant tumors in the world [1]
We performed RT-PCR analysis to quantify full-length 2.0-kb CR-1 transcript (FL-CR-1) and SF-CR1 mRNA levels in HCC cell lines and tissues using primer sets that detect FLCR1 mRNA (UND/UNB) and total CR-1 mRNA (UNA/UNB) (Figure 1A)
Our results demonstrated that CR-1 overexpression in the mouse liver tissues and HCC cells significantly activated AKT, Stat3, ERK, and JNK pathways, which are closely associated with hepatocyte proliferation, liver regeneration and hepatocellular carcinogenesis
Summary
Hepatocellular carcinoma (HCC) accounts for 70–85% of all primary liver cancer cases and is one of the most common malignant tumors in the world [1]. The development of HCC involves several epigenetic and genetic changes; environmental factors such as cytotoxic and DNA-damaging chemicals, and chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are common risk factors associated with HCC [4,5,6]. Aberrant activation of embryonic genes such as Oct-4 in adult tissues is frequently associated with several cancers [17,18,19]. CR-1 plays an oncogenic role in colorectal cancer [22], melanoma [23], and esophageal squamous cell carcinoma [24]
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