Central genetic alterations common to all HCV-positive, HBV-positive and non-B, non-C hepatocellular carcinoma: A new approach to identify novel tumor markers

Abstract

Abstract. Hepatocellular carcinoma (HCC) is a common malignancy, but the prognosis remains poor due to the lack of sensitive diagnostic markers. To gain insight into the central molecular features common to all types of HCC, and to identify novel diagnostic markers or therapeutic targets for HCC, we performed a gene expression profiling analysis using a high throughput RT-PCR system. After examining the mRNA expression of 3,072 genes in 204 (119 tumor and 85 nontumor) liver samples, we identified differential gene expression between the HCV group (n=80), HBV group (n=19) and non-B, non-C group (n=20) with a principal component analysis and a correlation spectrum analysis. After selection of genes differentially expressed between tumor and non-tumor tissues (p<0.01) within each HCC group, a total of 51 differentially expressed genes (23 upregulated and 28 downregulated genes) were found to be common to the three HCC groups. Gene Ontology grouping analysis revealed that genes with functions related to cell proliferation or differentiation and genes encoding extracellular proteins were found to be significantly enriched in these 51 common genes. Using an Atelocollagenbased cell transfection array for functional analysis of eight upregulated genes, five (CANX, FAM34A, PVRL2, LAMR1, and GBA) significantly inhibited cellular apoptosis by two independent assays. In conclusion, we identified 51 differentially expressed genes, common to all HCC types. Among these genes, there was a high incidence of anti-apoptotic activity. This combination approach with the advanced statistical methods and the bioinformatical analysis may be useful for finding novel molecular targets for diagnosis and therapy.

Elucidating Novel Hepatitis C Virus–Host Interactions Using Combined Mass Spectrometry and Functional Genomics Approaches

“…In the IP 3xFLAG-NS2 condition, eight interactants were identified that included hepatitis B virus X-interacting protein (HBxIP) as the most enriched host protein (supplemental Table S3). Most of the identified NS2 partners were novel, including the protein calnexin, which was identified as an HCV cofactor in an RNAi screen (18) and characterized as a cell apoptosis inhibitor induced in HCV-positive hepatocellular carcinoma (36). The IP-NS3/4A showed the greatest number of interacting partners on silver staining gel, and this was reflected in the MS/MS analysis with a total of 33 statistically enriched hits.…”

PVRL2 is translocated to the TRA@ locus in t(14;19)(q11;q13)‐positive peripheral T‐cell lymphomas

“…PVRL2 has been previously suggested to play a role in the pathogenesis of acute myeloid leukemia via mediating extramedullar manifestations or influencing intracellular interactions between malignant and immunoreactive cells (Graf et al, 2005). Furthermore, gene expression profiling performed on hepatocellular carcinomas revealed an up-regulation of PVRL2, which was supposed to participate in the inhibition of apoptosis in hepatoma cells (Kurokawa et al, 2006).…”

Differential gene expression profiles of hepatocellular carcinomas associated or not with viral infection

“…Although many studies have reported differential gene expression profile in HCC (4,8,9,17,18), the 6 genes previously reported to be associated with HCC had not been identified in the literature comparing viral and non-viral HCC. In a similar study, Kurokawa et al (18) found a total of 51 genes that were identified as differentially expressed between tumor and non-tumor tissues regardless of the etiology of HCC. It is thought that these genes may play significant roles in the development of cancer independent of hepatitis viruses.…”

“…Multiple studies linking hepatitis viruses and chemical carcinogens to hepatocarcinogenesis have provided clues for the understanding of this molecular system (16). Several reports have differentially identified expressed genes in HCC using oligo-microarrays (17,18). Although genomic approaches have yielded global gene expression profiles in HCC and have identified a number of candidate genes as biomarkers useful for cancer staging, the prediction of prognosis and treatment selection (8) remain unclear across all subsets of HCC (19).…”