Abstract
Liver cancer is very common worldwide and the rates of hepatocellular carcinoma (HCC) have increased by over 70% in the last 2 decades in the US. Late diagnosis, because of the lack of clinical symptoms, and decreased hepatic function, because of underlying hepatic disease, lead to the extremely high mortality rates associated with HCC. Clearly, the identification of markers that are expressed early in the development of HCC and that are easily detected in high-risk patients would aid in early diagnosis and increased survival. We present the cloning and characterization of a novel gene, CRG-L2 (Cancer related gene-Liver 2), which displays high expression in murine and human hepatocellular carcinomas. Using in situ hybridization, we show that CRG-L2 mRNA levels are increased early during the development of liver tumors in C3H/HeJ mice, and that in normal tissues CRG-L2 mRNA is restricted to the murine testis and human placenta. Its restricted expression in normal tissues and unique early upregulation during tumor development make CRG-L2 an excellent candidate as a new clinical marker of HCC.
Highlights
Primary liver cancer is the fifth most common cancer worldwide with approximately half a million cases reported in 1990
The low level of expression in the Cancer related gene-Liver 2 (CRG-L2), a new marker for liver tumor development CR Graveel et al regenerating livers suggested the possibility that the increased expression was tumor specific and would not occur in nontumorigenic proliferative states of human liver, such as cirrhosis or hepatitis
Key characteristics of an effective hepatocellular carcinoma (HCC) marker include a significant expression change in comparison with normal liver, deregulation in early stages of hepatocarcinogenesis, lack of response to proliferation caused by noncancerous conditions, limited expression in normal tissues, and the ability to be detected in body fluids
Summary
Primary liver cancer is the fifth most common cancer worldwide with approximately half a million cases reported in 1990. To identify novel markers of HCC, we started with a mouse model because of the many disadvantages of using human tissue. We demonstrated that diethylnitrosamine (DEN)-treated C3 H/HeJ mice develop liver tumors that provide a representative model for human HCC (Graveel et al, 2001). We cloned a novel gene that is upregulated in the mouse liver tumors and showed that the human homolog of this gene displays increased expression in human liver tumors (Graveel et al, 2001). Owing to the similarity between gene expression in the livers of DEN-treated mice and human HCC, we have cloned and characterized CRG-L2 (Cancer related gene-Liver 2), a novel gene that corresponds to an mRNA fragment obtained using representational difference analysis to compare normal liver and liver tumors obtained from DEN-treated C3H/HeJ mice. We show that CRG-L2 is upregulated in both mouse and human HCC, and that it possesses characteristics that suggest that it may be a potential new clinical marker for HCC and other cancers
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