URGs, the novel therapeutic targets for HCC

B47

1. Cloning and functional study of novel genes 
 Chronic hepatitis B, which is closely related to the development of cirrhosis and HCC, is a major public health problem worldwide (Jie Liu, et al. The Lancet 2007). By cDNA subtraction and RACE-PCR full length cloning, totally 4 novel genes which are related to HBV have been successfully cloned by our group.
 (1) Novel gene URG7: 745bp in full length, encoding a protein of 99 amino acids(published in Hepatology 2001). Functional study showed that this novel gene could stimulate cell growth, and also against Fas-mediated TNF killing in NF-κB dependant way.
 (2) Novel gene URG4: 3607bp in length, encoding a 104kD protein (published in Neoplasia 2002). Homology analysis showed that this gene is on Chromosome 7,which has 34% homologous with caspase recruitment domain family 6. Initial study showed that URG4 ,as a novel oncogene, could stimulate cell growth by through cyclin D (published in Neoplasia 2006).
 (3) Novel gene URG11: 3074 bp in length, encoding a 673 amino acids protein (published in Neoplasia 2003). Homology analysis demonstrated that URG11 is on Chromosome 11, without any homology with known genes. Functional study reveled that this gene could stimulate cell growth by up-regulating β-catenin expression (published in Hepatology 2006) with newly generated monoclonal antibody against URG11 (published in Hybridoma 2006).
 (4) HuSui1: 1370 bp in length, encoding 113 amino acids, is on human Chromosome17 (published in Oncogene 1999). The finding that HBx downregulating HuSui1 could induce malignant transformation of host cells.
 (5) S15a: 535 bp in length, encoding a 130 amino acids protein (published in Molecular Carcinogenesis 2004). Initial study showed that this gene functions as a oncogene which could stimulate cell growth.
 (6) VEGFR-3(S): the short form splice variant of VEGFR-3 (published in Hepatology 2007). The function study showed that HBV may short circuit VEGFR-3(S) signaling in liver cancer, suggesting that blocking VEGFR-3(S) signaling may be effective in preventing tumor development.
 2. Predicting value of novel genes for HCC 
 A 15-year retrospective study in patients with liver cirrhosis showed that elevated expression of URG11, URG7, URG4, S15a, VEGFR-3(S)and HuSui1 in the canceration group compared with non-canceration group. Combinational serum screening or even single protein along can be served as early predictors for HCC, with prediction of HCC 2-3 years earlier (published in Cancer Research 2004). These genes can be also the prognostic markers in patients with HCC (published in Cancer Research 2004).
 3. Novel gene URG11-β-catenin pathway in HBV related HCC
 It was found that HBxAg could downregulate E-cadherin, the partner of β-catenin, both In Vivo and In Vitro by promoter methylation of E-cadherin (published in Oncogene 2006), and that HBx could stimulate Wnt signaling through URG11 and β-catenin, which contribiutes to the development of hepatocellular carcinoma (published in Hepatology 2006). These results were cited by Nat Rev Cancer 2007 as the mechanism whereby DNA virus contributes to the development of cancer.