Identification, using cDNA macroarray analysis, of distinct gene expression profiles associated with pathological and virological features of hepatocellular carcinoma

Delpuech, Oona; Trabut, Jean‐Baptiste; Carnot, Françoise; Feuillard, Jean; Bréchot, Christian; Kremsdorf, Dina

doi:10.1038/sj.onc.1205392

Cited by 85 publications

(77 citation statements)

References 76 publications

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“…As expected, the gene expression patterns were found to vary significantly among the HCC and normal liver samples. In concordance with previous publications (41,42), genes associated with cell proliferation and mitosis were found to have increased expression in HCC samples. In contrast, most genes that were expressed at lower levels in HCC than in normal liver tissues comprised genes specifically expressed in differentiated hepatocytes.…”

Section: Discussionsupporting

confidence: 79%

Genes Involved in Viral Carcinogenesis and Tumor Initiation in Hepatitis C Virus-Induced Hepatocellular Carcinoma

Mas

Maluf

Archer

et al. 2009

Mol Med

260

236

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The role of chronic hepatitis C virus (HCV) in the pathogenesis of HCV-associated hepatocellular carcinoma (HCC) remains controversial. To understand the transition from benign to malignant, we studied the gene expression patterns in liver tissues at different stages, including normal, cirrhosis, and different HCC stages. We studied 108 liver tissue samples obtained from 88 distinct patients (41 HCV-cirrhotic tissues, 17 HCV-cirrhotic tissues from patients with HCC, and 47 HCV-HCC tissues). Differentially expressed genes (DEG) were studied by use of high-density oligonucleotide arrays. Among probe sets identified as differentially expressed via the F test, all pairwise comparisons were performed. Cirrhotic tissues with and without concomitant HCC were further evaluated, and a classifier was used to predict whether the tissue type was associated with HCC. Differential expression profiles were analyzed using Interaction Networks and Functional Analysis. Characteristic gene signatures were identified when normal tissue was compared with cirrhosis, cirrhosis with early HCC, and normal with HCC. Pathway analysis classified the cellular and biological functions of the DEG as related to cellular growth and proliferation, cell death and inflammatory disease in cirrhosis; cell death, cell cycle, DNA replication, and immune response in early HCCs; and cell death, cell growth and proliferation, cell cycle, and DNA repair in advanced HCCs. Characteristic gene signatures were identified at different stages of HCV-HCC progression. A set of genes were identified to predict whether the cirrhotic tissue was associated with HCC.

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Section: Discussionsupporting

confidence: 79%

Genes Involved in Viral Carcinogenesis and Tumor Initiation in Hepatitis C Virus-Induced Hepatocellular Carcinoma

Mas

Maluf

Archer

et al. 2009

Mol Med

260

236

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“…A number of overexpressed genes encoding for secreted (e.g., GPC3, LCN2 and DKK1) or membrane-bound proteins (e.g., GPC3, IGSF1 and PSK-1), which may be attractive candidates for the diagnosis of HCC, have also been identified (Patil et al, 2005). In the analysis of 102 tumors from 82 HBV and HCV patients, Chen et al did not find any consistent distinction between the two groups, whereas other studies could identify at least some distinctive trends between HBV-and HCV-related HCCs (Iizuka et al, 2002;Delpuech et al, 2002). However, as for the study of viral genes, no specific gene signature has been found that might clearly explain as to how HBV or HCV mediates oncogenesis.…”

Section: Occult Hbv Infectionmentioning

confidence: 73%

Viral hepatitis and liver cancer: the case of hepatitis C

2006

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Chronic infection with the hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. The pathogenesis of HCC in HCV infection has extensively been analysed. Hepatitis C virus-induced chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation are considered as one of the major pathogenic mechanisms. Increasing experimental evidence suggests that HCV contributes to HCC by directly modulating pathways that promote the malignant transformation of hepatocytes. Hepatitis C virus is an RNA virus that does not integrate into the host genome but HCV proteins interact with many host-cell factors well beyond their roles in the viral life cycle and are involved in a wide range of activities, including cell signaling, transcription, cell proliferation, apoptosis, membrane rearrangements, vesicular trafficking and translational regulation. At least four of the HCV gene products, namely HCV core, NS3, NS4B and NS5A, have been shown to exhibit transformation potential in tissue culture and several potentially oncogenic pathways have been shown to be altered by the expression of HCV proteins. Both HCV core and NS5A induce the accumulation of wild-type b-catenin and the Wnt-b-catenin pathway emerges as a common target for HCV (and HBV) in human HCCs, also independently from axin/b-catenin gene mutations. Induction of both endoplasmic reticulum stress and oxidative stress by HCV proteins might also contribute to HCV transformation. Most of the putative transforming functions of the HCV proteins have been defined in artificial cellular systems, which may not be applicable to HCV infection in vivo, and still need to be established in relevant infection and disease models.

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“…Evidence is accumulating to the fact that alterations of the Wnt/b-catenin pathway, due or unrelated to b-catenin gene mutation, is a common event in hepatocarcinogenesis and is associated with the clinical and pathological features of the disease (Hsu et al, 2000;Devereux et al, 2001;Laurent-Puig et al, 2001;Wong et al, 2001;Inagawa et al, 2002). As to the PKC and JNK pathways, their role and prevalence of activation remain poorly known in human hepatocarcinogenesis, although some studies have underlined their potentially oncogenic properties (Delpuech et al, 2002;Guo et al, 2005;Wu et al, 2008). In this study, we did observe an increment in activity of one or more of the three WNT/FZD potentially dependent pathways (b-catenin, PKC, and JNK) in a majority of HCCs with the accumulation of dysregulations of WNT/FZD elements and the absence of b-catenin gene mutation, by comparison to their matched pT.…”

Section: Discussionmentioning

confidence: 99%

Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma

et al. 2008

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Dysregulation of growth factors and their receptors is central to human hepatocellular carcinoma (HCC). We previously demonstrated that the Frizzled-7 membrane receptor mediating the Wnt signalling can activate the b-catenin pathway and promotes malignancy in human hepatitis B virus-related HCCs. Expression patterns of all the 10 Frizzled receptors, and their extracellular soluble autoparacrine regulators (19 Wnt activators and 4 sFRP inhibitors) were assessed by real-time RT -PCR in 62 human HCC of different etiologies and their matched peritumorous areas. Immunostaining was performed to localise Frizzled on cell types in liver tissues. Regulation of three known Frizzled-dependent pathways (b-catenin, protein kinase C, and C-Jun NH 2 -terminal kinase) was measured in tissues by western blot. We found that eight Frizzled-potentially activating events were pleiotropically dysregulated in 95% HCC and 68% peritumours as compared to normal livers (upregulations of Frizzled-3/6/7 and Wnt3/4/5a, or downregulation of sFRP1/5), accumulating gradually with severity of fibrosis in peritumours and loss of differentiation status in tumours. The hepatocytes supported the Wnt/Frizzled signalling since specifically overexpressing Frizzled receptors in liver tissues. Dysregulation of the eight Frizzled-potentially activating events was associated with differential activation of the three known Frizzled-dependent pathways. This study provides an extensive analysis of the Wnt/Frizzled receptor elements and reveals that the dysregulation may be one of the most common and earliest events described thus far during hepatocarcinogenesis.

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Identification, using cDNA macroarray analysis, of distinct gene expression profiles associated with pathological and virological features of hepatocellular carcinoma

Cited by 85 publications

References 76 publications

Genes Involved in Viral Carcinogenesis and Tumor Initiation in Hepatitis C Virus-Induced Hepatocellular Carcinoma

Genes Involved in Viral Carcinogenesis and Tumor Initiation in Hepatitis C Virus-Induced Hepatocellular Carcinoma

Viral hepatitis and liver cancer: the case of hepatitis C

Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma

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